XYLANASE VARIANTS AND POLYNUCLEOTIDES ENCODING SAME
20230017381 · 2023-01-19
Assignee
Inventors
- Rakhi Saikia (Bangalore, IN)
- Amol Vaijanathappa Shivange (Pasadena, CA, US)
- Sohel Dalal (Juhapura, IN)
- Kenneth Jensen (Juhapura, DK)
- Lars Olsen (Valby, DK)
- Kristian Bertel Romer M. Krogh (Bagsvaerd, DK)
- Madelyn Mallison Shoup (Raleigh, NC, US)
- Bernardo Vidal, JR. (Wake Forest, NC, US)
Cpc classification
C12P19/04
CHEMISTRY; METALLURGY
C12Y302/01004
CHEMISTRY; METALLURGY
D21C5/005
TEXTILES; PAPER
C12N9/2402
CHEMISTRY; METALLURGY
C12P19/14
CHEMISTRY; METALLURGY
C12P21/02
CHEMISTRY; METALLURGY
International classification
C12P19/04
CHEMISTRY; METALLURGY
Abstract
The present invention relates to xylanase variants of a parent xylanase having increased thermostability when compared to the parent xylanase. The present invention also relates to polynucleotides encoding the variants, nucleic acid constructs, vectors, and host cells comprising the polynucleotides, and method of producing the variants of the present invention.
Claims
1. A xylanase variant of a parent xylanase comprising a substitution at one or more positions corresponding to position 45, 149, 364, 258, 276, and 388 of SEQ ID NO: 1 and wherein said variant has xylanase activity and wherein said variant has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%, but less than 100% sequence identity sequence identity to the polypeptide of SEQ ID NO: 1.
2. The xylanase variant according to claim 1, which has increased thermostability compared to the xylanase of SEQ ID NO: 1.
3. The xylanase variant according to claim 1, wherein said increased thermostability is measured as increased melting temperature using TSA of at least 0.5° C., at least 1° C., at least 1.5° C., at least 2° C., at least 2.5° C., at least 3° C., at least 3.5° C., at least 4.0° C., at least 4.5° C. or at least 5° C.
4. The xylanase variant according to claim 1 further comprising a substitution at one or more positions corresponding to position to 9, 11, 18, 19, 20, 24, 25, 28, 40, 60, 61, 69, 70, 77, 79, 92, 93, 95, 113, 117, 127, 161, 163, 168, 170, 173, 180, 187, 190, 192, 211, 214, 215, 219, 234, 243, 250, 252, 260, 281, 282, 286, 314, 334, 340, 350, 355, 356, 358, 366, 375, 384, 385, 386, 389, 391, 393, 394, 395, 396, 446, 459, 468, 469, 470, 471, 472, 473, 474, 476, 477, 478, 480, 481, 483, 484, 495, 496, 497, 498, 499, 500, 501, 503, 522, 525, 526, 527, 528, 529, 530, and 540 of SEQ ID NO: 1.
5. The xylanase variant according to claim 4, wherein said variant comprises one or more of the following substitutions at a position corresponding to positions D9, D11, A18, S19, A20, A24, A25, M28, C40, V45, C60, Q61, C69, T70, Q77, A79, S92, A93, D95, D113, A117, N127, L149, C161, N163, N168, A170, S173, T180, G187, S190, D192, T211, S214, T215, H219, V234, W250, A252, V258, N260, A276, L281, S282, A286, Q314, H334, A340, V350, N355, L356, H358, A364, T366, C375, Q384, Q385, Y386, S388, S389, Y391, V393, G394, N395, C396, D446, R459, C468, I469, D470, L471, A472, A472, S473, S473, N474, N476, T477, L478, T480, S481, R483, L484, W495, Q496, V497, V498, A499, V500, S501, G503, C522, D525, G526, N527, S528, N529, L530 and C540 of SEQ ID NO: 1.
6. The xylanase variant according to claim 5, wherein said variant comprises one or more of the following substitutions at a position corresponding to positions D9E, D11E, A18V, 519T, A20H, A20P, A24H, A24K, A25W, M28P, C40A, C40L, C40S, C40V, C60A, C60L, C60S, C60V, Q61K, Q61R, C69A, C69L, C69S, C69V, T70R, Q77E, A79C, S92D, S92N, A93S, A93T, D95N, D113T, A117C, A117S, N127D, C161L, C161S, C161V, N163H, N168G, A170S, S173Y, T180Q, G187K, G187L, G187S, S190E, D192E, T211H, S214E, S214Q, S214Y, T215I, T215K, T215V, H219I, H219V, V234P, C243L, C243S, C243V, W250Y, A252S, N260H, L281V, S282N, A286E, A286S, Q314A, H334D, A340G, V350L, N355G, L356M, H358D, H358T, T366I, T366V, C375A, C375L, C375S, C375V, Q384A, Q385C, Y386G, S389H, S389V Y391V, V393H, V393R, G394A, G394D, G394Q, N395D, C396A, C396L, C396A, C396S, C396V, D446T, R459V, 0468A, C468L, C468S, C468V, 1469T, D470A, D470K, D470T, D470V, L471R, A472I, A472L, S473G, S473K, N474G, N476D, N476N, T477K, T477V, L478N, L478P, T480L, T480N, S481A, R483V, L484D, L484K, L484S, W495E, W495I, W495S, Q496E, Q496W, Q496R, V497D, V497E, V497P, V497W, V498I, A499L, A499Y, V500T, S501E, 5501N, G503L, C522A, C522S, C522V, D525L, G526T, N527H, S528H, N529T, L530R, C540A, C540L, C540S, and C540V of SEQ ID NO: 1.
7. A method of producing a xylanase variant according to claim 1, comprising cultivating the host cell under conditions conducive for production of the polypeptide and further comprising recovering the polypeptide.
8. A method of obtaining a xylanase variant, comprising (a) introducing into a parent xylanase a substitution at one or more positions corresponding to positions 45, 149, 364, 258, 276, and 388 of SEQ ID NO: 1, wherein the xylanase variant has xylanase activity and has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%, but less than 100% sequence identity to SEQ ID NO: 1; and (b) optionally recovering the xylanase variant.
9. A composition comprising the xylanase variant of claims-1.
10. A method for increasing the starch yield and/or gluten yield from corn kernels in a wet milling process, the method comprising contacting corn kernels or a fraction of the corn kernels, particularly a fiber rich fraction, with an effective amount of xylanase variant of claim 1 and optionally one or more hydrolytic enzymes.
11. The method according to claim 10, comprising the steps of: a) soaking the corn kernels in water to produce soaked kernels; b) grinding the soaked kernels to produce ground kernels; c) separating germ from the ground kernels to produce a corn kernel mass comprising fiber, starch and gluten; and d) subjecting the corn kernel mass to a fiber washing procedure separating starch and gluten from the fiber; wherein at least a xylanase variant of claim 1 is present/added before or during step d).
12. The method of claim 11, further comprising the steps of: e) separating the starch from the gluten; and optionally f) washing the starch.
13. The method according to claim 10, wherein the one or more hydrolytic enzymes comprises one or more cellulases.
14. The method according to claim 13, wherein the cellulase(s) comprises one or more enzyme selected from the group consisting of an endoglucanase (EG), and a cellobiohydrolase (CBH).
15. (canceled)
Description
DETAILED DESCRIPTION OF THE INVENTION
[0088] The present invention relates to xylanase variants of a parent xylanase comprising a substitution at one or more positions corresponding to positions: 45, 149, 364, 258, 276, and 388 of SEQ ID NO: 1 and wherein said variant has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%, but less than 100% sequence identity to the polypeptide of SEQ ID NO: 1, and wherein said variant has xylanase activity.
[0089] The present invention relates to xylanase variants of a parent xylanase further comprises a substitution at one or more positions corresponding to positions: 9, 11, 18, 19, 20, 24, 25, 28, 40, 60, 61, 69, 70, 77, 79, 92, 93, 95, 113, 117, 127, 161, 163, 168, 170, 173, 180, 187, 190, 192, 211, 214, 215, 219, 234, 243, 250, 252, 260, 281, 282, 286, 314, 334, 340, 350, 355, 356, 358, 366, 375, 384, 385, 386, 389, 391, 393, 394, 395, 396, 446, 459, 468, 469, 470, 471, 472, 473, 474, 476, 477, 478, 480, 481, 483, 484, 495, 496, 497, 498, 499, 500, 501, 503, 522, 525, 526, 527, 528, 529, 530, and 540 of SEQ ID NO: 1 and wherein said variant has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%, but less than 100% sequence identity to the polypeptide of SEQ ID NO: 1, and wherein said variant has xylanase activity.
[0090] In one aspect, present invention relates to xylanase variants comprising a substitution at one or more positions corresponding to positions: 45, 149, 364, 258, 276, and 388 of SEQ ID NO: 1; and wherein said variant has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%, but less than 100% sequence identity to the polypeptide of SEQ ID NO: 1, and wherein said variant has xylanase activity and wherein the xylanase variant has an improved property compared to the xylanase of SEQ ID NO: 1.
[0091] In one aspect, present invention relates to xylanase variants further comprises a substitution at one or more positions corresponding to positions: 9, 11, 18, 19, 20, 24, 25, 28, 40, 60, 61, 69, 70, 77, 79, 92, 93, 95, 113, 117, 127, 161, 163, 168, 170, 173, 180, 187, 190, 192, 211, 214, 215, 219, 234, 243, 250, 252, 260, 281, 282, 286, 314, 334, 340, 350, 355, 356, 358, 366, 375, 384, 385, 386, 389, 391, 393, 394, 395, 396, 446, 459, 468, 469, 470, 471, 472, 473, 474, 476, 477, 478, 480, 481, 483, 484, 495, 496, 497, 498, 499, 500, 501, 503, 522, 525, 526, 527, 528, 529, 530, and 540 of SEQ ID NO: 1; and wherein said variant has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%, but less than 100% sequence identity to the polypeptide of SEQ ID NO: 1, and wherein said variant has xylanase activity and wherein the xylanase variant has an improved property relative to said parent.
[0092] The invention relates to xylanase variants having one or more substitutions having an improved property, such as improved (increased) thermostability.
[0093] In one aspect, present invention relates to xylanase variants comprising a substitution at one or more positions corresponding to positions: 45, 149, 364, 258, 276, and 388 of SEQ ID NO: 1; and wherein said variant has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%, but less than 100% sequence identity to the polypeptide of SEQ ID NO: 1, and wherein said variant has xylanase activity and wherein the xylanase variant has increased thermostability compared to the xylanase of SEQ ID NO: 1.
[0094] In one aspect, present invention relates to xylanase variants further comprises a substitution at one or more positions corresponding to positions: 9, 11, 18, 19, 20, 24, 25, 28, 40, 60, 61, 69, 70, 77, 79, 92, 93, 95, 113, 117, 127, 161, 163, 168, 170, 173, 180, 187, 190, 192, 211, 214, 215, 219, 234, 243, 250, 252, 260, 281, 282, 286, 314, 334, 340, 350, 355, 356, 358, 366, 375, 384, 385, 386, 389, 391, 393, 394, 395, 396, 446, 459, 468, 469, 470, 471, 472, 473, 474, 476, 477, 478, 480, 481, 483, 484, 495, 496, 497, 498, 499, 500, 501, 503, 522, 525, 526, 527, 528, 529, 530, and 540 of SEQ ID NO: 1; and wherein said variant has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%, but less than 100% sequence identity to the polypeptide of SEQ ID NO: 1, and wherein said variant has xylanase activity and wherein the xylanase variant has increased thermostability compared to the xylanase of SEQ ID NO: 1.
Xylanase Variants
[0095] The present invention provides xylanase variants of a parent xylanase comprising a substitution at one or more positions corresponding to position 45, 149, 364, 258, 276, and 388 of SEQ ID NO: 1 and wherein said variant has increased thermostability compared to the xylanase of SEQ ID NO: 1.
[0096] The present invention also provides xylanase variants of a parent xylanase further comprising a substitution at one or more positions corresponding to position 9, 11, 18, 19, 20, 24, 25, 28, 40, 60, 61, 69, 70, 77, 79, 92, 93, 95, 113, 117, 127, 161, 163, 168, 170, 173, 180, 187, 190, 192, 211, 214, 215, 219, 234, 243, 250, 252, 260, 281, 282, 286, 314, 334, 340, 350, 355, 356, 358, 366, 375, 384, 385, 386, 389, 391, 393, 394, 395, 396, 446, 459, 468, 469, 470, 471, 472, 473, 474, 476, 477, 478, 480, 481, 483, 484, 495, 496, 497, 498, 499, 500, 501, 503, 522, 525, 526, 527, 528, 529, 530, and 540 of SEQ ID NO: 1 and wherein said variant has increased thermostability compared to the xylanase of SEQ ID NO: 1.
[0097] In one aspect, the variant has sequence identity of at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%, but less than 100% to the amino acid sequence of the parent alpha-amylase.
[0098] In one aspect, the variant has a sequence identity of at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%, but less than 100% to SEQ ID NO: 1.
[0099] In one aspect, the substituted amino acid residue is different from the naturally-occurring amino acid residue in that position. In one embodiment, the substitution is selected from the group consisting of A, C, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W and Y, with the proviso that the substituted amino acid residue is different from the naturally-occurring amino acid residue in that position.
[0100] In one aspect, the number of substitutions is 1-50, e.g., 1-45, 1-40, 1-35, 1-30, 1-25, 1-20, 1-15, 1-10 or 1-5, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 or 50 substitutions.
[0101] In another aspect, a variant comprises a substitution at two or more positions corresponding to any of positions 45, 149, 364, 258, 276, and 388 of SEQ ID NO: 1 and wherein said variant has xylanase activity and further wherein said variant has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%, but less than 100% sequence identity sequence identity to the polypeptide of SEQ ID NO: 1.
[0102] In another aspect, a variant comprises a substitution at three or more positions corresponding to any of positions 45, 149, 364, 258, 276, and 388 of SEQ ID NO: 1 and wherein said variant has xylanase activity and further wherein said variant has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%, but less than 100% sequence identity sequence identity to the polypeptide of SEQ ID NO: 1.
[0103] In another aspect, a variant comprises a substitution at four or more positions corresponding to any of positions 45, 149, 364, 258, 276, and 388 of SEQ ID NO: 1 and wherein said variant has xylanase activity and further wherein said variant has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%, but less than 100% sequence identity sequence identity to the polypeptide of SEQ ID NO: 1.
[0104] In another aspect, a variant comprises a substitution at five or more positions corresponding to any of positions 45, 149, 364, 258, 276, and 388 of SEQ ID NO: 1 and wherein said variant has xylanase activity and further wherein said variant has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%, but less than 100% sequence identity sequence identity to the polypeptide of SEQ ID NO: 1.
[0105] In another aspect, a variant comprises a substitution at six or more positions corresponding to any of positions 45, 149, 364, 258, 276, and 388 of SEQ ID NO: 1 and wherein said variant has xylanase activity and further wherein said variant has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%, but less than 100% sequence identity sequence identity to the polypeptide of SEQ ID NO: 1.
[0106] In another aspect, a variant comprises a substitution at each position corresponding to any of positions 45, 149, 364, 258, 276, and 388 of SEQ ID NO: 1 and wherein said variant has xylanase activity and further wherein said variant has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%, but less than 100% sequence identity sequence identity to the polypeptide of SEQ ID NO: 1.
[0107] In another aspect, a variant comprises a substitution at two or more positions corresponding to any of positions 45, 149, 364, 258, 276, 388, 9, 11, 18, 19, 20, 24, 25, 28, 40, 60, 61, 69, 70, 77, 79, 92, 93, 95, 113, 117, 127, 161, 163, 168, 170, 173, 180, 187, 190, 192, 211, 214, 215, 219, 234, 243, 250, 252, 260, 281, 282, 286, 314, 334, 340, 350, 355, 356, 358, 366, 375, 384, 385, 386, 389, 391, 393, 394, 395, 396, 446, 459, 468, 469, 470, 471, 472, 473, 474, 476, 477, 478, 480, 481, 483, 484, 495, 496, 497, 498, 499, 500, 501, 503, 522, 525, 526, 527, 528, 529, 530, and 540 of SEQ ID NO: 1 and wherein said variant has xylanase activity and further wherein said variant has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%, but less than 100% sequence identity sequence identity to the polypeptide of SEQ ID NO: 1.
[0108] In another aspect, a variant comprises a substitution at three or more positions corresponding to any of positions 45, 149, 364, 258, 276, 388, 9, 11, 18, 19, 20, 24, 25, 28, 40, 60, 61, 69, 70, 77, 79, 92, 93, 95, 113, 117, 127, 161, 163, 168, 170, 173, 180, 187, 190, 192, 211, 214, 215, 219, 234, 243, 250, 252, 260, 281, 282, 286, 314, 334, 340, 350, 355, 356, 358, 366, 375, 384, 385, 386, 389, 391, 393, 394, 395, 396, 446, 459, 468, 469, 470, 471, 472, 473, 474, 476, 477, 478, 480, 481, 483, 484, 495, 496, 497, 498, 499, 500, 501, 503, 522, 525, 526, 527, 528, 529, 530, and 540 of SEQ ID NO: 1 and wherein said variant has xylanase activity and further wherein said variant has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%, but less than 100% sequence identity sequence identity to the polypeptide of SEQ ID NO: 1.
[0109] In another aspect, a variant comprises a substitution at four or more positions corresponding to any of positions 45, 149, 364, 258, 276, 388, 9, 11, 18, 19, 20, 24, 25, 28, 40, 60, 61, 69, 70, 77, 79, 92, 93, 95, 113, 117, 127, 161, 163, 168, 170, 173, 180, 187, 190, 192, 211, 214, 215, 219, 234, 243, 250, 252, 260, 281, 282, 286, 314, 334, 340, 350, 355, 356, 358, 366, 375, 384, 385, 386, 389, 391, 393, 394, 395, 396, 446, 459, 468, 469, 470, 471, 472, 473, 474, 476, 477, 478, 480, 481, 483, 484, 495, 496, 497, 498, 499, 500, 501, 503, 522, 525, 526, 527, 528, 529, 530, and 540 of SEQ ID NO: 1 and wherein said variant has xylanase activity and further wherein said variant has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%, but less than 100% sequence identity sequence identity to the polypeptide of SEQ ID NO: 1.
[0110] In another aspect, a variant comprises a substitution at five or more positions corresponding to any of positions 45, 149, 364, 258, 276, 388, 9, 11, 18, 19, 20, 24, 25, 28, 40, 60, 61, 69, 70, 77, 79, 92, 93, 95, 113, 117, 127, 161, 163, 168, 170, 173, 180, 187, 190, 192, 211, 214, 215, 219, 234, 243, 250, 252, 260, 281, 282, 286, 314, 334, 340, 350, 355, 356, 358, 366, 375, 384, 385, 386, 389, 391, 393, 394, 395, 396, 446, 459, 468, 469, 470, 471, 472, 473, 474, 476, 477, 478, 480, 481, 483, 484, 495, 496, 497, 498, 499, 500, 501, 503, 522, 525, 526, 527, 528, 529, 530, and 540 of SEQ ID NO: 1 and wherein said variant has xylanase activity and further wherein said variant has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%, but less than 100% sequence identity sequence identity to the polypeptide of SEQ ID NO: 1.
[0111] In another aspect, a variant comprises a substitution at six or more positions corresponding to any of positions 45, 149, 364, 258, 276, 388, 9, 11, 18, 19, 20, 24, 25, 28, 40, 60, 61, 69, 70, 77, 79, 92, 93, 95, 113, 117, 127, 161, 163, 168, 170, 173, 180, 187, 190, 192, 211, 214, 215, 219, 234, 243, 250, 252, 260, 281, 282, 286, 314, 334, 340, 350, 355, 356, 358, 366, 375, 384, 385, 386, 389, 391, 393, 394, 395, 396, 446, 459, 468, 469, 470, 471, 472, 473, 474, 476, 477, 478, 480, 481, 483, 484, 495, 496, 497, 498, 499, 500, 501, 503, 522, 525, 526, 527, 528, 529, 530, and 540 of SEQ ID NO: 1 and wherein said variant has xylanase activity and further wherein said variant has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%, but less than 100% sequence identity sequence identity to the polypeptide of SEQ ID NO: 1.
[0112] In another aspect, a variant comprises a substitution at seven or more positions corresponding to any of positions 45, 149, 364, 258, 276, 388, 9, 11, 18, 19, 20, 24, 25, 28, 40, 60, 61, 69, 70, 77, 79, 92, 93, 95, 113, 117, 127, 161, 163, 168, 170, 173, 180, 187, 190, 192, 211, 214, 215, 219, 234, 243, 250, 252, 260, 281, 282, 286, 314, 334, 340, 350, 355, 356, 358, 366, 375, 384, 385, 386, 389, 391, 393, 394, 395, 396, 446, 459, 468, 469, 470, 471, 472, 473, 474, 476, 477, 478, 480, 481, 483, 484, 495, 496, 497, 498, 499, 500, 501, 503, 522, 525, 526, 527, 528, 529, 530, and 540 of SEQ ID NO: 1 and wherein said variant has xylanase activity and further wherein said variant has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%, but less than 100% sequence identity sequence identity to the polypeptide of SEQ ID NO: 1.
[0113] In another aspect, a variant comprises a substitution at eight or more positions corresponding to any of positions 45, 149, 364, 258, 276, 388, 9, 11, 18, 19, 20, 24, 25, 28, 40, 60, 61, 69, 70, 77, 79, 92, 93, 95, 113, 117, 127, 161, 163, 168, 170, 173, 180, 187, 190, 192, 211, 214, 215, 219, 234, 243, 250, 252, 260, 281, 282, 286, 314, 334, 340, 350, 355, 356, 358, 366, 375, 384, 385, 386, 389, 391, 393, 394, 395, 396, 446, 459, 468, 469, 470, 471, 472, 473, 474, 476, 477, 478, 480, 481, 483, 484, 495, 496, 497, 498, 499, 500, 501, 503, 522, 525, 526, 527, 528, 529, 530, and 540 of SEQ ID NO: 1 and wherein said variant has xylanase activity and further wherein said variant has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%, but less than 100% sequence identity sequence identity to the polypeptide of SEQ ID NO: 1.
[0114] In another aspect, a variant comprises a substitution at nine or more positions corresponding to any of positions 45, 149, 364, 258, 276, 388, 9, 11, 18, 19, 20, 24, 25, 28, 40, 60, 61, 69, 70, 77, 79, 92, 93, 95, 113, 117, 127, 161, 163, 168, 170, 173, 180, 187, 190, 192, 211, 214, 215, 219, 234, 243, 250, 252, 260, 281, 282, 286, 314, 334, 340, 350, 355, 356, 358, 366, 375, 384, 385, 386, 389, 391, 393, 394, 395, 396, 446, 459, 468, 469, 470, 471, 472, 473, 474, 476, 477, 478, 480, 481, 483, 484, 495, 496, 497, 498, 499, 500, 501, 503, 522, 525, 526, 527, 528, 529, 530, and 540 of SEQ ID NO: 1 and wherein said variant has xylanase activity and further wherein said variant has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%, but less than 100% sequence identity sequence identity to the polypeptide of SEQ ID NO: 1.
[0115] In another aspect, a variant comprises a substitution at ten or more positions corresponding to any of positions 45, 149, 364, 258, 276, 388, 9, 11, 18, 19, 20, 24, 25, 28, 40, 60, 61, 69, 70, 77, 79, 92, 93, 95, 113, 117, 127, 161, 163, 168, 170, 173, 180, 187, 190, 192, 211, 214, 215, 219, 234, 243, 250, 252, 260, 281, 282, 286, 314, 334, 340, 350, 355, 356, 358, 366, 375, 384, 385, 386, 389, 391, 393, 394, 395, 396, 446, 459, 468, 469, 470, 471, 472, 473, 474, 476, 477, 478, 480, 481, 483, 484, 495, 496, 497, 498, 499, 500, 501, 503, 522, 525, 526, 527, 528, 529, 530, and 540 of SEQ ID NO: 1 and wherein said variant has xylanase activity and further wherein said variant has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%, but less than 100% sequence identity sequence identity to the polypeptide of SEQ ID NO: 1.
[0116] In another aspect, a variant comprises a substitution at each position corresponding to positions 45, 149, 364, 258, 276, 388, 9, 11, 18, 19, 20, 24, 25, 28, 40, 60, 61, 69, 70, 77, 79, 92, 93, 95, 113, 117, 127, 161, 163, 168, 170, 173, 180, 187, 190, 192, 211, 214, 215, 219, 234, 243, 250, 252, 260, 281, 282, 286, 314, 334, 340, 350, 355, 356, 358, 366, 375, 384, 385, 386, 389, 391, 393, 394, 395, 396, 446, 459, 468, 469, 470, 471, 472, 473, 474, 476, 477, 478, 480, 481, 483, 484, 495, 496, 497, 498, 499, 500, 501, 503, 522, 525, 526, 527, 528, 529, 530, and 540 of SEQ ID NO: 1 and wherein said variant has xylanase activity and wherein said variant has xylanase activity and further wherein said variant has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%, but less than 100% sequence identity sequence identity to the polypeptide of SEQ ID NO: 1.
[0117] In one aspect, a variant comprises one or more of the following substitutions at positions corresponding to positions: D9, D11, A18, S19, A20, A24, A25, M28, C40, V45, C60, Q61, C69, T70, Q77, A79, S92, A93, D95, D113, A117, N127, L149, C161, N163, N168, A170, S173, T180, G187, S190, D192, T211, S214, T215, H219, V234, W250, A252, V258, N260, A276, L281, S282, A286, Q314, H334, A340, V350, N355, L356, H358, A364, T366, C375, Q384, Q385, Y386, S388, S389, Y391, V393, G394, N395, C396, D446, R459, C468, 1469, D470, L471, A472, A472, S473, S473, N474, N476, T477, L478, T480, S481, R483, L484, W495, Q496, V497, V498, A499, V500, S501, G503, C522, D525, G526, N527, S528, N529, L530 and C540 of SEQ ID NO: 1 and wherein said variant has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%, but less than 100% sequence identity to the polypeptide of SEQ ID NO: 1.
[0118] In one aspect, a variant comprises one or more of the following substitutions at positions corresponding to positions D9E, D11E, A18V, 519T, A20H, A20P, A24H, A24K, A25W, M28P, C40A, C40L, C40S, C40V, V45C, V45I, V45L, V45N, V45T, C60A, C60L, C60S, C60V, Q61K, Q61R, C69A, C69L, C69S, C69V, T70R, Q77E, A79C, S92D, S92N, A93S, A93T, D95N, D113T, A117C, A117S, N127D, L149R, C161L, C161S, C161V, N163H, N168G, A170S, S173Y, T180Q, G187K, G187L, G187S, S190E, D192E, T211H, S214E, S214Q, S214Y, T215I, T215K, T215V, H219I, H219V, V234P, C243L, C243S, C243V, W250Y, A252S, V258P, V258R, N260H, A276C, A276D, A276F, A276N, A276Q, A276S, A276T, L281V, S282N, A286E, A286S, Q314A, H334D, A340G, V350L, N355G, L356M, H358D, H358T, A364G, T366I, T366V, C375A, C375L, C375S, C375V, Q384A, Q385C, Y386G, 5388A, S388H, S388K, S388L, 5388R, S389H, S389V, Y391V, V393H, V393R, G394A, G394D, G394Q, N395D, C396A, C396L, C396A, C396S, C396V, D446T, R459V, C468A, C468L, C468S, C468V, 1469T, D470A, D470K, D470T, D470V, L471R, A472I, A472L, S473G, S473K, N474G, N476D, T477K, T477V, L478N, L478P, T480L, T480N, S481A, R483V, L484D, L484K, L484S, W495E, W495I, W495S, Q496E, Q496W, Q496R, V497D, V497E, V497P, V497W, V498I, A499L, A499Y, V500T, S501E, 5501N, G503L, C522A, C522S, C522V, D525L, G526T, N527H, S528H, N529T, L530R, C540A, C540L, C540S, and C540V of SEQ ID NO: 1 and wherein said variant has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%, but less than 100% sequence identity to the polypeptide of SEQ ID NO: 1.
[0119] In another aspect, the variant comprises or consists of a substitution at a position corresponding to position 9 of SEQ ID NO: 1. In another aspect, the amino acid at a position corresponding to position 9 is substituted with Ala, Arg, Asn, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another aspect, the variant comprises or consists of the substitution D9E of the polypeptide of SEQ ID NO: 1.
[0120] In another aspect, the variant comprises or consists of a substitution at a position corresponding to position 11 of SEQ ID NO: 1. In another aspect, the amino acid at a position corresponding to position 3 is substituted with Ala, Arg, Asn, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another aspect, the variant comprises or consists of the substitution D11E of the polypeptide of SEQ ID NO: 1.
[0121] In another aspect, the variant comprises or consists of a substitution at a position corresponding to position 18 of SEQ ID NO: 1. In another aspect, the amino acid at a position corresponding to position 18 is substituted with Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another aspect, the variant comprises or consists of the substitution A18V of the polypeptide of SEQ ID NO: 1.
[0122] In another aspect, the variant comprises or consists of a substitution at a position corresponding to position 19 of SEQ ID NO: 1. In another aspect, the amino acid at a position corresponding to position 19 is substituted with Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Thr, Trp, Tyr, or Val. In another aspect, the variant comprises or consists of the substitution 519T of the polypeptide of SEQ ID NO: 1.
[0123] In another aspect, the variant comprises or consists of a substitution at a position corresponding to position 20 of SEQ ID NO: 1. In another aspect, the amino acid at a position corresponding to position 20 is substituted with Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another aspect, the variant comprises or consists of the substitution A20H or A20P of the polypeptide of SEQ ID NO: 1.
[0124] In another aspect, the variant comprises or consists of a substitution at a position corresponding to position 24 of SEQ ID NO: 1. In another aspect, the amino acid at a position corresponding to position 24 is substituted with Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another aspect, the variant comprises or consists of the substitution A24H or A24K of the polypeptide of SEQ ID NO: 1.
[0125] In another aspect, the variant comprises or consists of a substitution at a position corresponding to position 25 of SEQ ID NO: 1. In another aspect, the amino acid at a position corresponding to position 25 is substituted with Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another aspect, the variant comprises or consists of the substitution A25W of the polypeptide of SEQ ID NO: 1.
[0126] In another aspect, the variant comprises or consists of a substitution at a position corresponding to position 28 of SEQ ID NO: 1. In another aspect, the amino acid at a position corresponding to position 28 is substituted with Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another aspect, the variant comprises or consists of the substitution M28P of the polypeptide of SEQ ID NO: 1.
[0127] In another aspect, the variant comprises or consists of a substitution at a position corresponding to position 40 of SEQ ID NO: 1. In another aspect, the amino acid at a position corresponding to position 40 is substituted with Ala, Arg, Asn, Asp, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another aspect, the variant comprises or consists of the substitution C40A or C40L or C40S or C40V of the polypeptide of SEQ ID NO: 1.
[0128] In another aspect, the variant comprises or consists of a substitution at a position corresponding to position 45 of SEQ ID NO: 1. In another aspect, the amino acid at a position corresponding to position 45 is substituted with Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, or Tyr. In another aspect, the variant comprises or consists of the substitution V45C or V45I or V45L, V45N or V45T of the polypeptide of SEQ ID NO: 1.
[0129] In another aspect, the variant comprises or consists of a substitution at a position corresponding to position 60 of SEQ ID NO: 1. In another aspect, the amino acid at a position corresponding to position 60 is substituted with Ala, Arg, Asn, Asp, Gin, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another aspect, the variant comprises or consists of the substitution C60A or C60L or C60S or C60V of the polypeptide of SEQ ID NO: 1.
[0130] In another aspect, the variant comprises or consists of a substitution at a position corresponding to position 61 of SEQ ID NO: 1. In another aspect, the amino acid at a position corresponding to position 61 is substituted with Ala, Arg, Asn, Asp, Cys, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another aspect, the variant comprises or consists of the substitution Q61K or Q61R of the polypeptide of SEQ ID NO: 1.
[0131] In another aspect, the variant comprises or consists of a substitution at a position corresponding to position 69 of SEQ ID NO: 1. In another aspect, the amino acid at a position corresponding to position 69 is substituted with Ala, Arg, Asn, Asp, Gin, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another aspect, the variant comprises or consists of the substitution C69A or C69L or C69S or C69V of the polypeptide of SEQ ID NO: 1.
[0132] In another aspect, the variant comprises or consists of a substitution at a position corresponding to position 70 of SEQ ID NO: 1. In another aspect, the amino acid at a position corresponding to position 70 is substituted with Ala, Arg, Asn, Asp, Cys, Gin, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Trp, Tyr, or Val. In another aspect, the variant comprises or consists of the substitution T70R of the polypeptide of SEQ ID NO: 1.
[0133] In another aspect, the variant comprises or consists of a substitution at a position corresponding to position 77 of SEQ ID NO: 1. In another aspect, the amino acid at a position corresponding to position 77 is substituted with Ala, Arg, Asn, Asp, Cys, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another aspect, the variant comprises or consists of the substitution Q77E of the polypeptide of SEQ ID NO: 1.
[0134] In another aspect, the variant comprises or consists of a substitution at a position corresponding to position 79 of SEQ ID NO: 1. In another aspect, the amino acid at a position corresponding to position 79 is substituted with Arg, Asn, Asp, Cys, Gin, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another aspect, the variant comprises or consists of the substitution A79C of the polypeptide of SEQ ID NO: 1.
[0135] In another aspect, the variant comprises or consists of a substitution at a position corresponding to position 92 of SEQ ID NO: 1. In another aspect, the amino acid at a position corresponding to position 92 is substituted with Ala, Arg, Asn, Asp, Cys, Gin, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Thr, Trp, Tyr, or Val. In another aspect, the variant comprises or consists of the substitution S92D or S92N of the polypeptide of SEQ ID NO: 1.
[0136] In another aspect, the variant comprises or consists of a substitution at a position corresponding to position 93 of SEQ ID NO: 1. In another aspect, the amino acid at a position corresponding to position 93 is substituted with Arg, Asn, Asp, Cys, Gin, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another aspect, the variant comprises or consists of the substitution A93S or A93T of the polypeptide of SEQ ID NO: 1.
[0137] In another aspect, the variant comprises or consists of a substitution at a position corresponding to position 95 of SEQ ID NO: 1. In another aspect, the amino acid at a position corresponding to position 95 is substituted with Ala, Arg, Asn, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another aspect, the variant comprises or consists of the substitution D95N of the polypeptide of SEQ ID NO: 1.
[0138] In another aspect, the variant comprises or consists of a substitution at a position corresponding to position 113 of SEQ ID NO: 1. In another aspect, the amino acid at a position corresponding to position 113 is substituted with Ala, Arg, Asn, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another aspect, the variant comprises or consists of the substitution D113T of the polypeptide of SEQ ID NO: 1.
[0139] In another aspect, the variant comprises or consists of a substitution at a position corresponding to position 117 of SEQ ID NO: 1. In another aspect, the amino acid at a position corresponding to position 117 is substituted with Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another aspect, the variant comprises or consists of the substitution A117C or A117S of the polypeptide of SEQ ID NO: 1.
[0140] In another aspect, the variant comprises or consists of a substitution at a position corresponding to position 127 of SEQ ID NO: 1. In another aspect, the amino acid at a position corresponding to position 127 is substituted with Ala, Arg, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another aspect, the variant comprises or consists of the substitution N127D of the polypeptide of SEQ ID NO: 1.
[0141] In another aspect, the variant comprises or consists of a substitution at a position corresponding to position 149 of SEQ ID NO: 1. In another aspect, the amino acid at a position corresponding to position 149 is substituted with Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another aspect, the variant comprises or consists of the substitution L149R of the polypeptide of SEQ ID NO: 1.
[0142] In another aspect, the variant comprises or consists of a substitution at a position corresponding to position 161 of SEQ ID NO: 1. In another aspect, the amino acid at a position corresponding to position 161 is substituted with Ala, Arg, Asn, Asp, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another aspect, the variant comprises or consists of the substitution C161L or C161S or C161V of the polypeptide of SEQ ID NO: 1.
[0143] In another aspect, the variant comprises or consists of a substitution at a position corresponding to position 163 of SEQ ID NO: 1. In another aspect, the amino acid at a position corresponding to position 163 is substituted with Ala, Arg, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another aspect, the variant comprises or consists of the substitution N163H of the polypeptide of SEQ ID NO: 1.
[0144] In another aspect, the variant comprises or consists of a substitution at a position corresponding to position 168 of SEQ ID NO: 1. In another aspect, the amino acid at a position corresponding to position 168 is substituted with Ala, Arg, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another aspect, the variant comprises or consists of the substitution N168G of the polypeptide of SEQ ID NO: 1.
[0145] In another aspect, the variant comprises or consists of a substitution at a position corresponding to position 170 of SEQ ID NO: 1. In another aspect, the amino acid at a position corresponding to position 170 is substituted with Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another aspect, the variant comprises or consists of the substitution A1705 of the polypeptide of SEQ ID NO: 1.
[0146] In another aspect, the variant comprises or consists of a substitution at a position corresponding to position 173 of SEQ ID NO: 1. In another aspect, the amino acid at a position corresponding to position 173 is substituted with Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Thr, Trp, Tyr, or Val. In another aspect, the variant comprises or consists of the substitution S173Y of the polypeptide of SEQ ID NO: 1.
[0147] In another aspect, the variant comprises or consists of a substitution at a position corresponding to position 180 of SEQ ID NO: 1. In another aspect, the amino acid at a position corresponding to position 180 is substituted with Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Trp, Tyr, or Val. In another aspect, the variant comprises or consists of the substitution T180Q of the polypeptide of SEQ ID NO: 1.
[0148] In another aspect, the variant comprises or consists of a substitution at a position corresponding to position 187 of SEQ ID NO: 1. In another aspect, the amino acid at a position corresponding to position 187 is substituted with Ala, Arg, Asn, Asp, Cys, Gln, Glu, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another aspect, the variant comprises or consists of the substitution G187K or G187L or G187S of the polypeptide of SEQ ID NO: 1.
[0149] In another aspect, the variant comprises or consists of a substitution at a position corresponding to position 190 of SEQ ID NO: 1. In another aspect, the amino acid at a position corresponding to position 190 is substituted with Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Thr, Trp, Tyr, or Val. In another aspect, the variant comprises or consists of the substitution 5190E of the polypeptide of SEQ ID NO: 1.
[0150] In another aspect, the variant comprises or consists of a substitution at a position corresponding to position 192 of SEQ ID NO: 1. In another aspect, the amino acid at a position corresponding to position 192 is substituted with Ala, Arg, Asn, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another aspect, the variant comprises or consists of the substitution D192E of the polypeptide of SEQ ID NO: 1.
[0151] In another aspect, the variant comprises or consists of a substitution at a position corresponding to position 211 of SEQ ID NO: 1. In another aspect, the amino acid at a position corresponding to position 211 is substituted with Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Trp, Tyr, or Val. In another aspect, the variant comprises or consists of the substitution T211H of the polypeptide of SEQ ID NO: 1.
[0152] In another aspect, the variant comprises or consists of a substitution at a position corresponding to position 214 of SEQ ID NO: 1. In another aspect, the amino acid at a position corresponding to position 214 is substituted with Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Thr, Trp, Tyr, or Val. In another aspect, the variant comprises or consists of the substitution S214E or S214Q or S214Y of the polypeptide of SEQ ID NO: 1.
[0153] In another aspect, the variant comprises or consists of a substitution at a position corresponding to position 215 of SEQ ID NO: 1. In another aspect, the amino acid at a position corresponding to position 215 is substituted with Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Trp, Tyr, or Val. In another aspect, the variant comprises or consists of the substitution T215I or T215K or T215V of the polypeptide of SEQ ID NO: 1.
[0154] In another aspect, the variant comprises or consists of a substitution at a position corresponding to position 219 of SEQ ID NO: 1. In another aspect, the amino acid at a position corresponding to position 219 is substituted with Ala, Arg, Asn, Asp, Cys, Gin, Glu, Gly, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another aspect, the variant comprises or consists of the substitution H219I or H219V of the polypeptide of SEQ ID NO: 1.
[0155] In another aspect, the variant comprises or consists of a substitution at a position corresponding to position 234 of SEQ ID NO: 1. In another aspect, the amino acid at a position corresponding to position 234 is substituted with Ala, Arg, Asn, Asp, Cys, Gin, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, or Tyr. In another aspect, the variant comprises or consists of the substitution V234P of the polypeptide of SEQ ID NO: 1.
[0156] In another aspect, the variant comprises or consists of a substitution at a position corresponding to position 243 of SEQ ID NO: 1. In another aspect, the amino acid at a position corresponding to position 243 is substituted with Ala, Arg, Asn, Asp, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another aspect, the variant comprises or consists of the substitution C243L or C243S or C243V of the polypeptide of SEQ ID NO: 1.
[0157] In another aspect, the variant comprises or consists of a substitution at a position corresponding to position 250 of SEQ ID NO: 1. In another aspect, the amino acid at a position corresponding to position 250 is substituted with Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Tyr, or Val. In another aspect, the variant comprises or consists of the substitution W250Y of the polypeptide of SEQ ID NO: 1.
[0158] In another aspect, the variant comprises or consists of a substitution at a position corresponding to position 252 of SEQ ID NO: 1. In another aspect, the amino acid at a position corresponding to position 252 is substituted with Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another aspect, the variant comprises or consists of the substitution A252S of the polypeptide of SEQ ID NO: 1.
[0159] In another aspect, the variant comprises or consists of a substitution at a position corresponding to position 258 of SEQ ID NO: 1. In another aspect, the amino acid at a position corresponding to position 258 is substituted with Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, or Tyr. In another aspect, the variant comprises or consists of the substitution V258P or V258R of the polypeptide of SEQ ID NO: 1.
[0160] In another aspect, the variant comprises or consists of a substitution at a position corresponding to position 260 of SEQ ID NO: 1. In another aspect, the amino acid at a position corresponding to position 260 is substituted with Ala, Arg, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another aspect, the variant comprises or consists of the substitution N260H of the polypeptide of SEQ ID NO: 1.
[0161] In another aspect, the variant comprises or consists of a substitution at a position corresponding to position 276 of SEQ ID NO: 1. In another aspect, the amino acid at a position corresponding to position 276 is substituted with Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another aspect, the variant comprises or consists of the substitution A276C or A276D or A276F or A276N or A276Q or A276S or A276T of the polypeptide of SEQ ID NO: 1.
[0162] In another aspect, the variant comprises or consists of a substitution at a position corresponding to position 281 of SEQ ID NO: 1. In another aspect, the amino acid at a position corresponding to position 281 is substituted with Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another aspect, the variant comprises or consists of the substitution L281V of the polypeptide of SEQ ID NO: 1.
[0163] In another aspect, the variant comprises or consists of a substitution at a position corresponding to position 282 of SEQ ID NO: 1. In another aspect, the amino acid at a position corresponding to position 282 is substituted with Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Thr, Trp, Tyr, or Val. In another aspect, the variant comprises or consists of the substitution S282N of the polypeptide of SEQ ID NO: 1.
[0164] In another aspect, the variant comprises or consists of a substitution at a position corresponding to position 286 of SEQ ID NO: 1. In another aspect, the amino acid at a position corresponding to position 286 is substituted with Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another aspect, the variant comprises or consists of the substitution A286E or A286S of the polypeptide of SEQ ID NO: 1.
[0165] In another aspect, the variant comprises or consists of a substitution at a position corresponding to position 314 of SEQ ID NO: 1. In another aspect, the amino acid at a position corresponding to position 314 is substituted with Ala, Arg, Asn, Asp, Cys, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another aspect, the variant comprises or consists of the substitution Q314A of the polypeptide of SEQ ID NO: 1.
[0166] In another aspect, the variant comprises or consists of a substitution at a position corresponding to position 334 of SEQ ID NO: 1. In another aspect, the amino acid at a position corresponding to position 334 is substituted with Ala, Arg, Asn, Asp, Cys, Gin, Glu, Gly, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another aspect, the variant comprises or consists of the substitution H334D of the polypeptide of SEQ ID NO: 1.
[0167] In another aspect, the variant comprises or consists of a substitution at a position corresponding to position 340 of SEQ ID NO: 1. In another aspect, the amino acid at a position corresponding to position 340 is substituted with Arg, Asn, Asp, Cys, Gln, Glu, Gly, Ile, Leu, Lys, Met, His, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another aspect, the variant comprises or consists of the substitution A340G of the polypeptide of SEQ ID NO: 1.
[0168] In another aspect, the variant comprises or consists of a substitution at a position corresponding to position 350 of SEQ ID NO: 1. In another aspect, the amino acid at a position corresponding to position 3 is substituted with Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, or Tyr. In another aspect, the variant comprises or consists of the substitution V350L of the polypeptide of SEQ ID NO: 1.
[0169] In another aspect, the variant comprises or consists of a substitution at a position corresponding to position 355 of SEQ ID NO: 1. In another aspect, the amino acid at a position corresponding to position 355 is substituted with Ala, Arg, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another aspect, the variant comprises or consists of the substitution N355G of the polypeptide of SEQ ID NO: 1.
[0170] In another aspect, the variant comprises or consists of a substitution at a position corresponding to position 356 of SEQ ID NO: 1. In another aspect, the amino acid at a position corresponding to position 356 is substituted with Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another aspect, the variant comprises or consists of the substitution L256M of the polypeptide of SEQ ID NO: 1.
[0171] In another aspect, the variant comprises or consists of a substitution at a position corresponding to position 358 of SEQ ID NO: 1. In another aspect, the amino acid at a position corresponding to position 358 is substituted with Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another aspect, the variant comprises or consists of the substitution H358D or H358T of the polypeptide of SEQ ID NO: 1.
[0172] In another aspect, the variant comprises or consists of a substitution at a position corresponding to position 364 of SEQ ID NO: 1. In another aspect, the amino acid at a position corresponding to position 364 is substituted with Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another aspect, the variant comprises or consists of the substitution A364G of the polypeptide of SEQ ID NO: 1.
[0173] In another aspect, the variant comprises or consists of a substitution at a position corresponding to position 366 of SEQ ID NO: 1. In another aspect, the amino acid at a position corresponding to position 366 is substituted with Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Trp, Tyr, or Val. In another aspect, the variant comprises or consists of the substitution T3661 or T366V of the polypeptide of SEQ ID NO: 1.
[0174] In another aspect, the variant comprises or consists of a substitution at a position corresponding to position 375 of SEQ ID NO: 1. In another aspect, the amino acid at a position corresponding to position 375 is substituted with Ala, Arg, Asn, Asp, Gin, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another aspect, the variant comprises or consists of the substitution C375A or C375L or C375S or C375V of the polypeptide of SEQ ID NO: 1.
[0175] In another aspect, the variant comprises or consists of a substitution at a position corresponding to position 384 of SEQ ID NO: 1. In another aspect, the amino acid at a position corresponding to position 384 is substituted with Ala, Arg, Asn, Asp, Cys, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another aspect, the variant comprises or consists of the substitution Q384A of the polypeptide of SEQ ID NO: 1.
[0176] In another aspect, the variant comprises or consists of a substitution at a position corresponding to position 385 of SEQ ID NO: 1. In another aspect, the amino acid at a position corresponding to position 385 is substituted with Ala, Arg, Asn, Asp, Cys, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another aspect, the variant comprises or consists of the substitution Q385C of the polypeptide of SEQ ID NO: 1.
[0177] In another aspect, the variant comprises or consists of a substitution at a position corresponding to position 386 of SEQ ID NO: 1. In another aspect, the amino acid at a position corresponding to position 386 is substituted with Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, or Val. In another aspect, the variant comprises or consists of the substitution Y386G of the polypeptide of SEQ ID NO: 1.
[0178] In another aspect, the variant comprises or consists of a substitution at a position corresponding to position 388 of SEQ ID NO: 1. In another aspect, the amino acid at a position corresponding to position 388 is substituted with Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Thr, Trp, Tyr, or Val. In another aspect, the variant comprises or consists of the substitution S388A or S388H or S388K or S388L or S388R of the polypeptide of SEQ ID NO: 1.
[0179] In another aspect, the variant comprises or consists of a substitution at a position corresponding to position 389 of SEQ ID NO: 1. In another aspect, the amino acid at a position corresponding to position 389 is substituted with Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Thr, Trp, Tyr, or Val. In another aspect, the variant comprises or consists of the substitution S389H or S389V of the polypeptide of SEQ ID NO: 1.
[0180] In another aspect, the variant comprises or consists of a substitution at a position corresponding to position 391 of SEQ ID NO: 1. In another aspect, the amino acid at a position corresponding to position 391 is substituted with Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, or Val. In another aspect, the variant comprises or consists of the substitution Y391Vof the polypeptide of SEQ ID NO: 1.
[0181] In another aspect, the variant comprises or consists of a substitution at a position corresponding to position 393 of SEQ ID NO: 1. In another aspect, the amino acid at a position corresponding to position 393 is substituted with Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, or Tyr. In another aspect, the variant comprises or consists of the substitution V393H or V393R of the polypeptide of SEQ ID NO: 1.
[0182] In another aspect, the variant comprises or consists of a substitution at a position corresponding to position 394 of SEQ ID NO: 1. In another aspect, the amino acid at a position corresponding to position 394 is substituted with Ala, Arg, Asn, Asp, Cys, Gln, Glu, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another aspect, the variant comprises or consists of the substitution G394A or G394D or G394Q of the polypeptide of SEQ ID NO: 1.
[0183] In another aspect, the variant comprises or consists of a substitution at a position corresponding to position 395 of SEQ ID NO: 1. In another aspect, the amino acid at a position corresponding to position 395 is substituted with Ala, Arg, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another aspect, the variant comprises or consists of the substitution N395D of the polypeptide of SEQ ID NO: 1.
[0184] In another aspect, the variant comprises or consists of a substitution at a position corresponding to position 396 of SEQ ID NO: 1. In another aspect, the amino acid at a position corresponding to position 396 is substituted with Ala, Arg, Asn, Asp, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another aspect, the variant comprises or consists of the substitution C396A or C396L or C396S or C396V of the polypeptide of SEQ ID NO: 1.
[0185] In another aspect, the variant comprises or consists of a substitution at a position corresponding to position 446 of SEQ ID NO: 1. In another aspect, the amino acid at a position corresponding to position 446 is substituted with Ala, Arg, Asn, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another aspect, the variant comprises or consists of the substitution D446T of the polypeptide of SEQ ID NO: 1.
[0186] In another aspect, the variant comprises or consists of a substitution at a position corresponding to position 459 of SEQ ID NO: 1. In another aspect, the amino acid at a position corresponding to position 459 is substituted with Ala, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another aspect, the variant comprises or consists of the substitution R459V of the polypeptide of SEQ ID NO: 1.
[0187] In another aspect, the variant comprises or consists of a substitution at a position corresponding to position 468 of SEQ ID NO: 1. In another aspect, the amino acid at a position corresponding to position 468 is substituted with Ala, Arg, Asn, Asp, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another aspect, the variant comprises or consists of the substitution 0468A or C468L or C468S or C468V of the polypeptide of SEQ ID NO: 1.
[0188] In another aspect, the variant comprises or consists of a substitution at a position corresponding to position 469 of SEQ ID NO: 1. In another aspect, the amino acid at a position corresponding to position 469 is substituted with Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another aspect, the variant comprises or consists of the substitution 1469T of the polypeptide of SEQ ID NO: 1.
[0189] In another aspect, the variant comprises or consists of a substitution at a position corresponding to position 470 of SEQ ID NO: 1. In another aspect, the amino acid at a position corresponding to position 470 is substituted with Ala, Arg, Asp, Cys, Gin, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another aspect, the variant comprises or consists of the substitution D470A or D470K or D470T or D470V of the polypeptide of SEQ ID NO: 1.
[0190] In another aspect, the variant comprises or consists of a substitution at a position corresponding to position 471 of SEQ ID NO: 1. In another aspect, the amino acid at a position corresponding to position 471 is substituted with Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another aspect, the variant comprises or consists of the substitution L471R of the polypeptide of SEQ ID NO: 1.
[0191] In another aspect, the variant comprises or consists of a substitution at a position corresponding to position 472 of SEQ ID NO: 1. In another aspect, the amino acid at a position corresponding to position 472 is substituted with Arg, Asn, Asp, Cys, Gin, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another aspect, the variant comprises or consists of the substitution A472I or A472L of the polypeptide of SEQ ID NO: 1.
[0192] In another aspect, the variant comprises or consists of a substitution at a position corresponding to position 473 of SEQ ID NO: 1. In another aspect, the amino acid at a position corresponding to position 473 is substituted with Ala, Arg, Asn, Asp, Cys, Gin, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Thr, Trp, Tyr, or Val. In another aspect, the variant comprises or consists of the substitution S473G or S473K of the polypeptide of SEQ ID NO: 1.
[0193] In another aspect, the variant comprises or consists of a substitution at a position corresponding to position 474 of SEQ ID NO: 1. In another aspect, the amino acid at a position corresponding to position 474 is substituted with Ala, Arg, Asp, Cys, Gin, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another aspect, the variant comprises or consists of the substitution N474G of the polypeptide of SEQ ID NO: 1.
[0194] In another aspect, the variant comprises or consists of a substitution at a position corresponding to position 476 of SEQ ID NO: 1. In another aspect, the amino acid at a position corresponding to position 476 is substituted with Ala, Arg, Asp, Cys, Gin, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another aspect, the variant comprises or consists of the substitution N476D of the polypeptide of SEQ ID NO: 1.
[0195] In another aspect, the variant comprises or consists of a substitution at a position corresponding to position 477 of SEQ ID NO: 1. In another aspect, the amino acid at a position corresponding to position 477 is substituted with Ala, Arg, Asn, Asp, Cys, Gin, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Trp, Tyr, or Val. In another aspect, the variant comprises or consists of the substitution T477K or T477V of the polypeptide of SEQ ID NO: 1.
[0196] In another aspect, the variant comprises or consists of a substitution at a position corresponding to position 478 of SEQ ID NO: 1. In another aspect, the amino acid at a position corresponding to position 478 is substituted with Ala, Arg, Asn, Asp, Cys, Gin, Glu, Gly, His, Ile, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another aspect, the variant comprises or consists of the substitution L478N or L478P of the polypeptide of SEQ ID NO: 1.
[0197] In another aspect, the variant comprises or consists of a substitution at a position corresponding to position 480 of SEQ ID NO: 1. In another aspect, the amino acid at a position corresponding to position 480 is substituted with Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Trp, Tyr, or Val. In another aspect, the variant comprises or consists of the substitution T480L or T480N of the polypeptide of SEQ ID NO: 1.
[0198] In another aspect, the variant comprises or consists of a substitution at a position corresponding to position 481 of SEQ ID NO: 1. In another aspect, the amino acid at a position corresponding to position 481 is substituted with Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Thr, Trp, Tyr, or Val. In another aspect, the variant comprises or consists of the substitution S481A of the polypeptide of SEQ ID NO: 1.
[0199] In another aspect, the variant comprises or consists of a substitution at a position corresponding to position 483 of SEQ ID NO: 1. In another aspect, the amino acid at a position corresponding to position 483 is substituted with Ala, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another aspect, the variant comprises or consists of the substitution R483V of the polypeptide of SEQ ID NO: 1.
[0200] In another aspect, the variant comprises or consists of a substitution at a position corresponding to position 484 of SEQ ID NO: 1. In another aspect, the amino acid at a position corresponding to position 484 is substituted with Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another aspect, the variant comprises or consists of the substitution L484D or L484K or L484S of the polypeptide of SEQ ID NO: 1.
[0201] In another aspect, the variant comprises or consists of a substitution at a position corresponding to position 495 of SEQ ID NO: 1. In another aspect, the amino acid at a position corresponding to position 495 is substituted with Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Tyr, or Val. In another aspect, the variant comprises or consists of the substitution W495E or W495I or W4955 of the polypeptide of SEQ ID NO: 1.
[0202] In another aspect, the variant comprises or consists of a substitution at a position corresponding to position 496 of SEQ ID NO: 1. In another aspect, the amino acid at a position corresponding to position 496 is substituted with Ala, Arg, Asn, Asp, Cys, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another aspect, the variant comprises or consists of the substitution Q496E or Q496W or Q496R of the polypeptide of SEQ ID NO: 1.
[0203] In another aspect, the variant comprises or consists of a substitution at a position corresponding to position 497 of SEQ ID NO: 1. In another aspect, the amino acid at a position corresponding to position 497 is substituted with Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, or Tyr. In another aspect, the variant comprises or consists of the substitution V497D or V497E or V497P or V497W of the polypeptide of SEQ ID NO: 1.
[0204] In another aspect, the variant comprises or consists of a substitution at a position corresponding to position 498 of SEQ ID NO: 1. In another aspect, the amino acid at a position corresponding to position 498 is substituted with Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, or Tyr. In another aspect, the variant comprises or consists of the substitution V498I of the polypeptide of SEQ ID NO: 1.
[0205] In another aspect, the variant comprises or consists of a substitution at a position corresponding to position 499 of SEQ ID NO: 1. In another aspect, the amino acid at a position corresponding to position 499 is substituted with Arg, Asn, Asp, Cys, Gin, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another aspect, the variant comprises or consists of the substitution A499L or A499Y of the polypeptide of SEQ ID NO: 1.
[0206] In another aspect, the variant comprises or consists of a substitution at a position corresponding to position 500 of SEQ ID NO: 1. In another aspect, the amino acid at a position corresponding to position 500 is substituted with Ala, Arg, Asn, Asp, Cys, Gin, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, or Tyr. In another aspect, the variant comprises or consists of the substitution V500T of the polypeptide of SEQ ID NO: 1.
[0207] In another aspect, the variant comprises or consists of a substitution at a position corresponding to position 501 of SEQ ID NO: 1. In another aspect, the amino acid at a position corresponding to position 501 is substituted with Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Thr, Trp, Tyr, or Val. In another aspect, the variant comprises or consists of the substitution 5501E or S501N of the polypeptide of SEQ ID NO: 1.
[0208] In another aspect, the variant comprises or consists of a substitution at a position corresponding to position 503 of SEQ ID NO: 1. In another aspect, the amino acid at a position corresponding to position 503 is substituted with Ala, Arg, Asn, Asp, Cys, Gln, Glu, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another aspect, the variant comprises or consists of the substitution G503L of the polypeptide of SEQ ID NO: 1.
[0209] In another aspect, the variant comprises or consists of a substitution at a position corresponding to position 522 of SEQ ID NO: 1. In another aspect, the amino acid at a position corresponding to position 522 is substituted with Ala, Arg, Asn, Asp, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another aspect, the variant comprises or consists of the substitution C522A or C522S or C522V of the polypeptide of SEQ ID NO: 1.
[0210] In another aspect, the variant comprises or consists of a substitution at a position corresponding to position 525 of SEQ ID NO: 1. In another aspect, the amino acid at a position corresponding to position 525 is substituted with Ala, Arg, Asn, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another aspect, the variant comprises or consists of the substitution D525L of the polypeptide of SEQ ID NO: 1.
[0211] In another aspect, the variant comprises or consists of a substitution at a position corresponding to position 526 of SEQ ID NO: 1. In another aspect, the amino acid at a position corresponding to position 526 is substituted with Ala, Arg, Asn, Asp, Cys, Gln, Glu, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another aspect, the variant comprises or consists of the substitution G526T of the polypeptide of SEQ ID NO: 1.
[0212] In another aspect, the variant comprises or consists of a substitution at a position corresponding to position 527 of SEQ ID NO: 1. In another aspect, the amino acid at a position corresponding to position 527 is substituted with Ala, Arg, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another aspect, the variant comprises or consists of the substitution N527H of the polypeptide of SEQ ID NO: 1.
[0213] In another aspect, the variant comprises or consists of a substitution at a position corresponding to position 528 of SEQ ID NO: 1. In another aspect, the amino acid at a position corresponding to position 528 is substituted with Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Thr, Trp, Tyr, or Val. In another aspect, the variant comprises or consists of the substitution S528H of the polypeptide of SEQ ID NO: 1.
[0214] In another aspect, the variant comprises or consists of a substitution at a position corresponding to position 529 of SEQ ID NO: 1. In another aspect, the amino acid at a position corresponding to position 529 is substituted with Ala, Arg, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another aspect, the variant comprises or consists of the substitution N529T of the polypeptide of SEQ ID NO: 1.
[0215] In another aspect, the variant comprises or consists of a substitution at a position corresponding to position 530 of SEQ ID NO: 1. In another aspect, the amino acid at a position corresponding to position 530 is substituted with Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another aspect, the variant comprises or consists of the substitution L530R of the polypeptide of SEQ ID NO: 1.
[0216] In another aspect, the variant comprises or consists of a substitution at a position corresponding to position 540 of SEQ ID NO: 1. In another aspect, the amino acid at a position corresponding to position 540 is substituted with Ala, Arg, Asn, Asp, Gin, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In another aspect, the variant comprises or consists of the substitution C540A or C540L or C5405 or C540V of the polypeptide of SEQ ID NO: 1.
[0217] In one aspect, a variant comprises at least one substitution at a position corresponding to positions selected from a group consisting of: Y386G, Q385C, A276S, A276C, A276Q, A276F, A79C, A276N, V45L, 519T, H358D, L149R, A25W, V45N, I469T, S388A, A276T, S388H, S92D, D525L, S214Q, A364G, S388L, S388R, S473G, S389V, A20H, W495E, Y386Y, V393H, G187L, Q61K, G187S, A286E, A276Y, V258P, Q496E, G394A, V393R, T366V, S389S, S92N, N527H, Q384A, V497D, D470T, A18V, Q496Q, Q496R, S214E, P362P, S389H, V258R, A276D, L281V, V45I, and A117C of SEQ ID NO: 1 and wherein said variant has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%, but less than 100% sequence identity to the polypeptide of SEQ ID NO: 1.
[0218] In one aspect, a variant comprises substitutions at positions corresponding to positions selected from a group consisting of: V45L+L149R, V45N+L149R, L149R+A364G, V258P+A276Q, V258P+A276S, A25W L+149R, V45L+A276S, A25W+A276S, V45L+A276Q, V45L+V258P, A25W+V258P, A25W+A276Q, L149R+W250Y, V45L+S388K, V45L+A364G, V45N+V258P, V258P+S388K, A25W+V45L, A276Q+S388K, W250Y+A276Q, A276S+S388K, A276Q+L281V, W250Y+A276S, A25W+S388K, A276S+L281V, G187S+A276Q, S92D+A276S, L149R+V258R, V45N+S388K, A25W+A364G, V258P+L281V, V258R+A276S, G187S+A276S, G187K+A276S, V45L+S92D, V45L+L281V, V45N+W250Y, V258R+A276Q, V45L+V258R, W250Y+S388K, V45N+G187K, A25W+V258R, G187K+S388K, A25W+S92D, L281V+S388K, V45N+V258R, L281V+A364G, S92D+A364G, A25W+G187S, A25W+G187K, W250Y+V258P, S92D+V258P, G187K+W250Y, V45N+S92D, G187S+A364G, G187S+L281V, G187S+S388K, G187S+V258R, S92D+G187S, V45L+D11E, L149R+S388K, L149R+D11E, A364G+D11E, and S388K+D11E of SEQ ID NO: 1 and wherein said variant has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%, but less than 100% sequence identity to the polypeptide of SEQ ID NO: 1.
[0219] In one aspect, a variant comprises substitutions at positions corresponding to positions selected from a group consisting of: V45L+L149R+V258P, V45L+L149R+A364G, V45L+L149R+W250Y, V45L+L149R+G187S, V45L+L149R+S282N, and V45L+S92D+L149R of SEQ ID NO: 1 and wherein said variant has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%, but less than 100% sequence identity to the polypeptide of SEQ ID NO: 1.
[0220] In one aspect, a variant comprises substitution at positions corresponding to positions selected from a group consisting of: V45L+L149R+A252S+H334D, V45L+L149R+S190E+D446T, V45L+L149R+V258P+A364G, V45L+L149R+A276Q+A364G, V45L+L149R+A276S+A364G, V45L+L149R+V258P+A276S, V45L+L149R L281V+A364G, L149R+V258P+A276S+A364G, V45L+V258P+A276S+A364G, A25W+V45L+L149R+A364G, V45L+L149R+V258R+A364G, V45L+L149R+G187K+A364G, V45L+L149R+G187S+A364G, and V45L+L149R+W250Y+A364G of SEQ ID NO: 1 and wherein said variant has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%, but less than 100% sequence identity to the polypeptide of SEQ ID NO: 1.
[0221] In one aspect, a variant comprises substitutions at positions corresponding to positions selected from a group consisting of: V45L+A93S+L149R+A252S+H334D, V45L+A93S+L149R+A252S+H334D, V45L+A93S+L149R+V234P+A252S, V45L+A93S+L149R+A252S+H334D, V45L+A93S L149R+A252S+H334D, V45L+A93S+L149R+A252S+H334D, V45L+L149R5190E+D446T+R459V, V45L+L149R+V258P+A276S A364G, V45L+L149R+V258P+A276Q+A364G, A25W+V45L+L149R+V258P+A276S, V45L+L149R+A276Q+L281V+A364G, V45L+L149R+A276Q+S282N+A364G, A25W+V45L+L149R+V258P+A276Q, V45L+T70R+L149R+A276Q+A364G, V45L+L149R+V258P+L281V+A364G, A25W+V45L+L149R A276Q+A364G, V45L+L149R+A276Q+Q314A+A364G, V45L+L149R+G187K+V258P+A364G, V45L+L149R+A276Q+A286E+A364G, V45L+L149R+A276Q+H358T+A364G, A25W+V45N+L149R+V258P+A276S, V45L+N127D+L149R+A276Q+A364G, V45L+L149R+W250Y+A276Q+A364G, V45L+L149R+W250Y+V258P+A364G, V45L+L149R+A276Q+A364G+S388K, A25W+V45L+L149R+V258P+A364G, V45L+L149R+N168G+A276Q+A364G, V45L+A117S+L149R+A276Q+A364G, A24K+V45L+L149R+A276Q+A364G, V45L+L149R+A276Q+A286S+A364G, V45L+L149R+A170S+A276Q+A364G, V45L+L149R+T180Q+A276Q+A364G, V45L+L149R+A276Q V350L+A364G, V45L+L149R+V258P+S282N+A364G, A25W+V45L+L149R+A276S+A364G, V45L+L149R+G187S+V258P+A364G, A25W+L149R+V258P+A276S+A364G, V45L+L149R+G187L+A276Q A364G, A25W+V45L+V258P+A276S+A364G, V45L+L149R+N260H+A276Q+A364G, V45L+L149R+W250Y+V258R+A364G, V45L+L149R+N163H+A276Q+A364G, V45L+S92D+L149R+A276Q+A364G, V45L+L149R+S173Y+A276Q+A364G, V45L+S92D+L149R+V258P+A364G, V45L+D113T+L149R+A276Q+A364G, V45L+L149R+G187S+V258R+A364G, V45L+L149R+V258R+A364G+S388K, V45L+L149R+G187K V258R+A364G, V45L+L149R+V258R+S282N+A364G, V45L+L149R+V258R+L281V+A364G, V45L+S92N+L149R+V258P+A364G, V45L+L149R+V258P+A364G+S388K, and V45L+S92N+L149R+V258R+A364G of SEQ ID NO: 1 and wherein said variant has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%, but less than 100% sequence identity to the polypeptide of SEQ ID NO: 1.
[0222] In one aspect, a variant comprises substitutions at positions corresponding to positions selected from a group consisting of: A25W+V45L+A79C+L149R+V258P+A276S, V45L+L149R+V258P+A276S+H358T+A364G, A25W+V45L+L149R+V258P+A276S+A364G, V45L+L149R+V258P+A276S+L281V+A364G, V45L+A93S+L149R+A252S+H334D+A340G, V45L+L149R+V258P+A276S+A364G+S388K, V45L+L149R+N168G+V258P+A276S+A364G, V45L+L149R+S173Y+V258P+A276S+A364G, V45L+A93S+L149R+A252S+H334D+A340G, A25W+V45L+L149R+V258P+A276S+H358T, A25W+V45L+L149R+V258P+A276Q+A364G, A25W+V45L+L149R+S214E+V258P+A276S, V45L+L149R+A170S+V258P+A276S+A364G, A25W+V45L+L149R+S214Q+V258P+A276S, A25W+V45L+L149R+V258P+A276S+S388K, V45L+A93S+L149R+V234P+A252S+H334D, V45L+N127D+L149R+V258P+A276S+A364G, V45L+L149R+W250Y+V258P+A276S+A364G, A25W+V45L+L149R+W250Y+A276Q+A364G, V45L+L149R+T180Q+V258P+A276S+A364G, V45L+L149R+V258P+A276S+Q314A+A364G, V45L+A117S+L149R+V258P+A276S+A364G, V45N+L149R+V258P+A276S+A364G+S388K, V45L+L149R+V258P+A276Q+L281V+A364G, A25W+V45L+L149R+V258P+A276S+Q314A, V45L+L149R+V258P+A276S+A286E+A364G, A25W+V45L+L149R+A276Q+L281V+A364G, A25W+V45L+L149R+V258P+A276S+A286E, A25W+V45L+L149R+V258P+A276S+L281V, A25W+V45L+D113T+L149R+V258P+A276S, A25W+V45L+L149R+T180Q+V258P+A276S, A25W+V45L+L149R+V258P+A276S+A286S, V45L+L149R+G187L+A276Q+L281V+A364G, V45L+L149R+A276Q+L281V+V350L+A364G, V45L+L149R+A276Q+L281V+A364G+S388K, A25W+V45L+S92D+L149R+V258P+A276S, A25W+V45L+L149R+G187L+V258P+A276S, A25W+V45L+L149R+W250Y+V258P+A276S, V45L+D113T+L149R+V258P+A276S+A364G, V45L+T70R+L149R+A276Q+L281V+A364G, V45L+S92D+L149R+A276Q+L281V+A364G, V45L+D113T+L149R+A276Q+L281V+A364G, V45L+L149R+A276Q+L281V+Q314A+A364G, A25W+V45L+Q61K+L149R+V258P+A276S, D9E+A25W+V45L+L149R+V258P+A276S, V45L+T70R+L149R+V258P+A276S+A364G, V45L+L149R+N163H+V258P+A276S+A364G, V45L+L149R+T180Q+A276Q+L281V+A364G, V45L+L149R+A276Q+L281V+A286S+A364G, A25W+V45L+L149R+A170S+V258P+A276S, A25W+V45L+T70R+L149R+V258P+A276S, V45L+L149R+N168G+A276Q+L281V+A364G, V45L+L149R+S173Y+A276Q+L281V+A364G, V45L+L149R+W250Y+A276Q+L281V+A364G, A25W+V45L+L149R+A276Q+A286E+A364G, A25W+V45L+L149R+A276Q+A364G+S388K, V45L+N127D+L149R+A276Q+L281V+A364G, V45L+L149R+A276Q+L281V+A286E+A364G, A25W+V45L+A117S+L149R+V258P+A276S, A24K+V45L+L149R+V258P+A276S+A364G, V45L+L149R+V258P+A276S+S282N+A364G, V45L+A117S+L149R+A276Q+L281V+A364G, V45L+L149R+N260H+A276Q+L281V+A364G, A25W+V45L+L149R+N168G+V258P+A276S, A25W+V45L+L149R+G187S+V258P+A276S, A25W+V45L+L149R+V258P+A276S+V350L, A25W+V45L+Q61R+L149R+V258P+A276S, V45N+L149R+V258P+A276S+L281V+A364G, A25W+V45L+L149R+V258P+A276S+S282N, A25W+V45L+L149R+S173Y+V258P+A276S, A25W+V45L+L149R+A276Q+A286S+A364G, A25W+V45L+L149R+T215V+V258P+A276S, A25W+V45L+L149R+T215I+V258P+A276S, A25W+V45L+L149R+T211H+V258P+A276S, V45L+L149R+V258P+A276S+V350L+A364G, A25W+V45L+D113T+L149R+A276Q+A364G, A25W+V45N+L149R+V258P+A276S+A364G, A25W+V45L+L149R+H219I+V258P+A276S, M28P+V45L+L149R+V258P+A276S+A364G, A25W+V45L+T70R+L149R+A276Q+A364G, A25W+V45L+L149R+A276Q+Q314A+A364G, A25W+V45L+L149R+S214Y+V258P+A276S, V45L+L149R+A276Q+L281V+H358T+A364G, A25W+V45L+L149R+H219V+V258P+A276S, D11E+A25W+V45L+L149R+V258P+A276S, A25W+V45L+A117S+L149R+A276Q+A364G, A25W+V45L+L149R+G187L+A276Q+A364G, V45N+L149R+V258P+A276S+H358T+A364G, A25W+V45L+L149R+N163H+A276Q+A364G, A25W+V45L+L149R+S173Y+A276Q+A364G, A25W+V45L+L149R+A276Q+S282N+A364G, A25W+V45L+L149R+A276Q+H358T+A364G, A25W+V45L+L149R+T180Q+A276Q+A364G, A25W+V45L+N127D+L149R+A276Q+A364G, A25W+V45L+L149R+A170S+A276Q+A364G, A25W+V45L+N127D+L149R+V258P+A276S, A25W+V45L+L149R+N168G+A276Q+A364G, A25W+V45L+L149R+N260H+A276Q+A364G, A25W+V45L+L149R+G187K+V258P+A276S, A25W+M28P+V45L+L149R+V258P+A276S, V45L+L149R+N163H+A276Q+L281V+A364G, V45L+L149R+G187L+V258P+A276S+A364G, A25W+V45L+L149R+A276Q+V350L+A364G, V45L+L149R+V258P+A276S+N355G+A364G, A25W+V45L+L149R+V258P+A276S+N355G, A25W+V45L+S92D+L149R+A276Q+A364G, and A25W+V45L+L149R+A276Q+N355G+A364G of SEQ ID NO: 1 and wherein said variant has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%, but less than 100% sequence identity to the polypeptide of SEQ ID NO: 1.
[0223] In one aspect, a variant comprises substitutions at positions corresponding to positions selected from a group consisting of: V45L+A79C+L149R+V258P+A276S+A364G+S388K, V45N+A79C+L149R+V258P+A276S+A364G+S388K, V45L+L149R+S214Q+V258P+A276S+H358D+A364G, A25W+V45L+A79C+L149R+V258P+A276S+A364G, V45L+A79C+L149R+V258P+A276S+L281V+A364G, A25W+V45L+L149R+S214E+V258P+A276S+A364G, V45L+L149R+S214Q+V258P+A276Q+A364G+S388K, V45N+L149R+S214Q+V258P+A276S+A364G+S388K, V45L+L149R+S214Q+V258P+A276S+A364G+S388K, V45L+L149R+S214E+V258P+A276S+H358T+A364G, A25W+V45L+L149R+S214E+V258P+A276Q+A364G, V45L+L149R+S214Q+V258P+A276S+L281V+A364G, V45L+N127D+L149R+V258P+A276S+A364G+S388K, V45L+L149R+V258P+A276S+H358T+A364G+S388K, V45L+L149R+G187L+V258P+A276S+A364G+S388K, V45L+L149R+W250Y+V258P+A276S+A364G+S388K, V45L+L149R+V258P+A276S+A286E+A364G+S388K, V45L+L149R+V258P+A276S+S282N+A364G+S388K, A25W+V45L+L149R+V258P+A276S+A364G+S388K, V45L+L149R+S214Q+V258P+A276S+H358T+A364G, A25W+V45L+L149R+S214Q+V258P+A276S+A364G, V45L+L149R+N168G+V258P+A276S+A364G+S388K, V45L+A117S+L149R+V258P+A276S+A364G+S388K, A25W+V45L+L149R+V258P+A276S+H358T+A364G, V45L+L149R+V258P+N260H+A276S+A364G+S388K, V45L+L149R+T215I+V258P+A276S+A364G+S388K, V45L+Q61K+L149R+V258P+A276S+H358T+A364G, V45L+L149R+V258P+A276S+Q314A+H358T+A364G, V45L+L149R+T180Q+V258P+A276S+A364G+S388K, V45L+L149R+V258P+A276S+Q314A+A364G+S388K, A25W+V45L+L149R+V258P+A276S+A286S+A364G, V45L+L149R+H219I+V258P+A276S+H358T+A364G, V45L+L149R+V258P+A276S+V350L+A364G+S388K, D11E+V45L+L149R+V258P+A276S+A364G+S388K, V45L+D113T+L149R+V258P+A276S+A364G+S388K, V45L+L149R+G187K+V258P+A276S+A364G+S388K, M28P+V45L+L149R+V258P+A276S+A364G+S388K, V45L+L149R+S173Y+V258P+A276S+A364G+S388K, A25W+V45L+L149R+V258P+A276S+Q314A+A364G, V45L+L149R+G187L+V258P+A276S+H358T+A364G, V45L+L149R+T215V+V258P+A276S+H358T+A364G, V45L+T70R+L149R+V258P+A276S+A364G+S388K, V45L+L149R+V258P+A276S+V350L+H358T+A364G, D9E+V45L+L149R+V258P+A276S+H358T+A364G, V45L+L149R+T211H+V258P+A276S+H358T+A364G, V45L+L149R+V258P+A276S+L281V+A364G+S388K, V45L+L149R+V258P+A276S+S282N+H358T+A364G, V45L+L149R+T215I+V258P+A276S+H358T+A364G, A25W+V45L+L149R+S173Y+V258P+A276S+A364G, V45L+Q61K+L149R+V258P+A276S+A364G+S388K, A25W+V45L+Q61K+L149R+V258P+A276S+A364G, V45L+L149R+S214E+V258P+A276S+L281V+A364G, V45L+L149R+V258P+A276S+A286E+H358T+A364G, D9E+V45L+L149R+V258P+A276S+A364G+S388K, V45L+S92D+L149R+V258P+A276S+A364G+S388K, A25W+V45L+L149R+V258P+A276S+A286E+A364G, V45L+L149R+N168G+V258P+A276S+L281V+A364G, V45L+Q61R+L149R+V258P+A276S+H358T+A364G, V45L+L149R+G187S+V258P+A276S+A364G+S388K, V45L+L149R+V258P+A276S+L281V+Q314A+A364G, V45L+L149R+V258P+A276S+L281V+H358T+A364G, V45L+L149R+A170S+V258P+A276S+H358T+A364G, V45L+L149R+A170S+V258P+A276S+A364G+S388K, V45L+L149R+T215V+V258P+A276S+A364G+S388K, V45L+L149R+V258P+A276Q+H358T+A364G+S388K, A25W+V45N+L149R+S214E+V258P+A276S+A364G, V45L+L149R+V258P+A276S+A286S+H358T+A364G, A25W+V45L+L149R+G187S+V258P+A276S+A364G, V45L+L149R+T180Q+V258P+A276S+L281V+A364G, V45L+S92D+L149R+V258P+A276S+L281V+A364G, V45L+Q61R+L149R+V258P+A276S+L281V+A364G, V45L+L149R+A170S+V258P+A276S+L281V+A364G, D11E+A25W+V45L+L149R+V258P+A276S+A364G, A25W+V45L+Q61R+L149R+V258P+A276S+A364G, A25W+V45L+L149R+T215V+V258P+A276S+A364G, D9E+V45L+L149R+V258P+A276S+L281V+A364G, A25W+V45L+L149R+V258P+A276S+V350L+A364G, V45L+L149R+H219V+V258P+A276S+L281V+A364G, V45L+L149R+T180Q+V258P+A276S+H358T+A364G, V45L+L149R+T215V+V258P+A276S+L281V+A364G, A25W+V45L+L149R+V258P+A276S+S282N+A364G, A25W+V45L+L149R+T215I+V258P+A276S+A364G, A25W+V45L+L149R+H219I+V258P+A276S+A364G, V45L+A117S+L149R+V258P+A276S+L281V+A364G, D9E+A25W+V45L+L149R+V258P+A276S+A364G, V45L+L149R+S214Y+V258P+A276S+A364G+S388K, A25W+V45L+L149R+T180Q+V258P+A276S+A364G, A25W+V45L+L149R+V258P+A276S+L281V+A364G, V45L+N127D+L149R+V258P+A276S+L281V+A364G, V45L+L149R+S173Y+V258P+A276S+H358T+A364G, V45L+Q61R+L149R+V258P+A276S+A364G+S388K, V45L+L149R+V258P+A276S+L281V+A286E+A364G, A25W+V45L+L149R+W250Y+V258P+A276S+A364G, A25W+V45L+L149R+V258P+N260H+A276S+A364G, V45L+L149R+V258P+A276S+L281V+V350L+A364G, A25W+V45L+L149R+A170S+V258P+A276S+A364G, V45L+L149R+V258P+A276S+L281V+A286S+A364G, V45L+L149R+V258P+A276S+L281V+S282N+A364G, D11E+V45L+L149R+V258P+A276S+L281V+A364G, V45L+Q61K+L149R+V258P+A276S+L281V+A364G, V45L+L149R+T215I+V258P+A276S+L281V+A364G, A25W+V45L+S92D+L149R+V258P+A276S+A364G, V45L+L149R+S214Y+V258P+A276S+L281V+A364G, V45L+L149R+T211H+V258P+A276S+L281V+A364G, A25W+V45L+L149R+G187L+V258P+A276S+A364G, V45L+S92D+L149R+V258P+A276S+H358T+A364G, V45L+L149R+G187K+V258P+A276S+H358T+A364G, V45L+L149R+N163H+V258P+A276S+L281V+A364G, A25W+V45L+T70R+L149R+V258P+A276S+A364G, V45L+L149R+S173Y+V258P+A276S+L281V+A364G, V45L+L149R+G187L+V258P+A276S+L281V+A364G, V45L+L149R+G187K+V258P+A276S+L281V+A364G, V45L+L149R+W250Y+V258P+A276S+H358T+A364G, V45L+L149R+T211H+V258P+A276S+A364G+S388K, V45L+L149R+N163H+V258P+A276S+A364G+S388K, V45L+L149R+V258P+A276S+A286S+A364G+S388K, A25W+V45L+L149R+S214Y+V258P+A276S+A364G, A25W+V45L+D113T+L149R+V258P+A276S+A364G, V45L+T70R+L149R+V258P+A276S+L281V+A364G, A25W+V45L+N127D+L149R+V258P+A276S+A364G, V45L+T70R+L149R+V258P+A276S+H358T+A364G, V45L+L149R+H219I+V258P+A276S+L281V+A364G, A25W+V45L+A117S+L149R+V258P+A276S+A364G, A25W+V45L+L149R+N168G+V258P+A276S+A364G, V45L+N127D+L149R+V258P+A276S+H358T+A364G, A25W+V45L+L149R+H219V+V258P+A276S+A364G, D11E+V45L+L149R+V258P+A276S+H358T+A364G, V45L+L149R+G187S+V258P+A276S+L281V+A364G, A25W+V45L+L149R+N163H+V258P+A276S+A364G, A25W+V45L+L149R+G187K+V258P+A276S+A364G, V45L+L149R+V258P+N260H+A276S+H358T+A364G, V45L+D113T+L149R+V258P+A276S+L281V+A364G, V45L+D113T+L149R+V258P+A276S+H358T+A364G, V45L+L149R+N168G+V258P+A276S+H358T+A364G, V45L+L149R+S214Y+V258P+A276S+H358T+A364G, V45L+A117S+L149R+V258P+A276S+H358T+A364G, A25W+M28P+V45L+L149R+V258P+A276S+A364G, M28P+V45L+L149R+V258P+A276S+L281V+A364G, M28P+V45L+L149R+V258P+A276S+H358T+A364G, V45L+L149R+N163H+V258P+A276S+H358T+A364G, V45L+L149R+T215K+V258P+A276S+H358T+A364G, V45L+L149R+H219I+V258P+A276S+A364G+S388K, V45L+L149R+T215K+V258P+A276S+A364G+S388K, V45L+L149R+W250Y+V258P+A276S+L281V+A364G, V45L+L149R+H219V+V258P+A276S+A364G+S388K, A25W+V45L+L149R+V258P+A276S+N355G+A364G, V45L+L149R+V258P+A276S+N355G+A364G+S388K, V45L+L149R+V258P+A276S+L281V+N355G+A364G, V45L+L149R+V258P+A276S+N355G+H358T+A364G, and V45L+L149R+H219V+V258P+A276S+H358T+A364G of SEQ ID NO: 1 and wherein said variant has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%, but less than 100% sequence identity to the polypeptide of SEQ ID NO: 1.
[0224] In one aspect, a variant comprises substitutions at positions corresponding to positions selected from a group consisting of: V45L+A79C+L149R+S214E+V258P+A276S+A364G+S388K, V45L+A79C+L149R+S214Q+V258P+A276S+A364G+S388K, V45L+A79C+L149R+V258P+A276S+Q314A+A364G+S388K, V45L+A79C+L149R+V258P+A276S+L281V+A364G+S388K, V45L+A79C+L149R+S173Y+V258P+A276S+A364G+S388K, V45L+A79C+L149R+G187K+V258P+A276S+A364G+S388K, V45L+Q61R+A79C+L149R+V258P+A276S+A364G+S388K, V45L+A79C+L149R+N168G+V258P+A276S+A364G+S388K, V45L+A79C+L149R+T215V+V258P+A276S+A364G+S388K, V45L+A79C+L149R+V258P+A276S+A286S+A364G+S388K, V45L+A79C+L149R+H219V+V258P+A276S+A364G+S388K, V45L+A79C+L149R+A170S+V258P+A276S+A364G+S388K, D11E+V45L+A79C+L149R+V258P+A276S+A364G+S388K, V45L+A79C+L149R+V258P+A276S+A286E+A364G+S388K, V45L+A79C+L149R+T180Q+V258P+A276S+A364G+S388K, V45L+A79C+L149R+H219I+V258P+A276S+A364G+S388K, V45L+L149R+S214E+V258P+A276S+H358D+A364G+D470T, V45L+A79C+L149R+V258P+A276S+V350L+A364G+S388K, V45L+L149R+S214E+V258P+A276S+H358D+A364G+D470T, V45L+A79C+D113T+L149R+V258P+A276S+A364G+S388K, V45L+A79C+N127D+L149R+V258P+A276S+A364G+S388K, D9E+V45L+A79C+L149R+V258P+A276S+A364G+S388K, V45L+L149R+S214E+V258P+A276S+H358D+A364G+D470T, V45L+A79C+L149R+W250Y+V258P+A276S+A364G+S388K, V45L+L149R+S214E+V258P+A276S+H358D+A364G+D470T, V45L+L149R+S214E+V258P+A276S+H358D+A364G+D470T, V45L+A79C+L149R+N163H+V258P+A276S+A364G+S388K, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G, A25W+V45L+A79C+L149R+S214E+V258P+A276S+A364G, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+D470T, V45L+A79C+S92D+L149R+V258P+A276S+A364G+S388K, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G, V45L+L149R+S214Q+V258P+A276S+A286E+A364G+S388K, V45L+L149R+S214Q+T215I+V258P+A276S+A364G+S388K, A25W+V45L+L149R+S214Q+V258P+A276S+A364G+S388K, V45L+L149R+A170S+S214Q+V258P+A276S+A364G+S388K, V45L+Q61K+L149R+S214Q+V258P+A276S+A364G+S388K, V45L+L149R+N168G+S214Q+V258P+A276S+A364G+S388K, V45L+A79C+D95D+L149R+V258P+A276S+A364G+S388K, V45L+Q77E+A79C+L149R+V258P+A276S+A364G+S388K, V45L+L149R+S214Q+V258P+A276S+S282N+A364G+S388K, V45L+L149R+S214Q+V258P+A276S+Q314A+A364G+S388K, V45L+T70R+L149R+S214Q+V258P+A276S+A364G+S388K, V45L+L149R+S214Q+W250Y+V258P+A276S+A364G+S388K, V45L+L149R+G187K+S214Q+V258P+A276S+A364G+S388K, V45L+L149R+V258P+A276S+L281V+H358T+A364G+S388K, M28P+V45L+L149R+S214Q+V258P+A276S+A364G+S388K, V45L+L149R+G187L+S214Q+V258P+A276S+A364G+S388K, V45L+L149R+S214Q+V258P+A276S+A286S+A364G+S388K, D9E+V45L+L149R+S214Q+V258P+A276S+A364G+S388K, V45L+L149R+S173Y+S214Q+V258P+A276S+A364G+S388K, V45L+A79C+L149R+V258P+A276S+H358T+A364G+S388K, A25W+V45L+L149R+S214E+V258P+A276S+H358T+A364G, A25W+V45L+L149R+S214E+V258P+A276S+A286E+A364G, A25W+V45L+Q61K+L149R+S214E+V258P+A276S+A364G, A25W+V45L+L149R+V258P+A276S+H358T+A364G+S388K, V45L+L149R+S214Q+V258P+A276S+V350L+A364G+S388K, D11E+V45L+L149R+S214Q+V258P+A276S+A364G+S388K, V45L+L149R+H219I+V258P+A276S+H358T+A364G+S388K, V45L+S92D+L149R+S214Q+V258P+A276S+A364G+S388K, A25W+V45L+L149R+T211H+S214E+V258P+A276S+A364G, A25W+V45L+L149R+S214E+H219V+V258P+A276S+A364G, V45L+L149R+W250Y+V258P+A276S+H358T+A364G+S388K, D9E+V45L+L149R+V258P+A276S+H358T+A364G+S388K, V45L+L149R+H219V+V258P+A276S+H358T+A364G+S388K, V45L+A117S+L149R+S214E+V258P+A276S+A364G+S388K, D11E+A25W+V45L+L149R+S214E+V258P+A276S+A364G, V45L+L149R+V258P+A276S+Q314A+H358T+A364G+S388K, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388L, V45L+L149R+T180Q+S214Q+V258P+A276S+A364G+S388K, V45L+D113T+L149R+S214Q+V258P+A276S+A364G+S388K, A25W+V45L+Q61R+L149R+S214E+V258P+A276S+A364G, A25W+V45L+L149R+S214E+V258P+A276S+L281V+A364G, D9E+A25W+V45L+L149R+S214E+V258P+A276S+A364G, V45L+Q61R+L149R+V258P+A276S+H358T+A364G+S388K, V45L+D113T+L149R+V258P+A276S+H358T+A364G+S388K, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388R, V45L+Q61R+L149R+S214Q+V258P+A276S+A364G+S388K, V45L+A117S+L149R+S214Q+V258P+A276Q+A364G+S388K, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K, V45L+L149R+T180Q+V258P+A276S+H358T+A364G+S388K, A25W+V45L+S92D+L149R+S214E+V258P+A276S+A364G, A25W+V45L+L149R+S214E+V258P+A276S+V350L+A364G, V45L+L149R+T211H+S214Q+V258P+A276S+A364G+S388K, A25W+V45L+L149R+S214E+H219I+V258P+A276S+A364G, V45L+L149R+T211H+V258P+A276S+H358T+A364G+S388K, A25W+V45L+A117S+L149R+S214E+V258P+A276S+A364G, A25W+V45L+L149R+S214E+T215V+V258P+A276S+A364G, V45L+A117S+L149R+V258P+A276S+H358T+A364G+S388K, V45L+L149R+N168G+V258P+A276S+H358T+A364G+S388K, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388H, A25W+V45L+L149R+S214E+T215I+V258P+A276S+A364G, V45L+N127D+L149R+V258P+A276S+H358T+A364G+S388K, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388A, V45N+A117S+L149R+S214Q+V258P+A276S+A364G+S388K, A25W+V45L+L149R+G187S+S214E+V258P+A276S+A364G, V45L+A117S+L149R+S214Y+V258P+A276S+A364G+S388K, A25W+V45L+L149R+S214E+V258P+A276S+A286S+A364G, V45L+L149R+V258P+A276S+A286S+H358T+A364G+S388K, V45L+L149R+S173Y+V258P+A276S+H358T+A364G+S388K, V45L+A79C+L149R+V258P+A276S+N355G+A364G+S388K, A25W+V45L+L149R+G187L+S214E+V258P+A276S+A364G, V45L+L149R+S214Q+V258P+A276S+L281V+A364G+S388K, V45L+L149R+S214Q+T215V+V258P+A276S+A364G+S388K, V45L+L149R+N163H+V258P+A276S+H358T+A364G+S388K, V45L+A79C+A117S+L149R+V258P+A276S+A364G+S388K, V45L+L149R+A170S+V258P+A276S+H358T+A364G+S388K, A25W+V45L+L149R+S214E+T215K+V258P+A276S+A364G, V45L+S92D+L149R+V258P+A276S+H358T+A364G+S388K, V45L+L149R+S214Q+V258P+A276S+N355G+A364G+S388K, A25W+V45L+L149R+S214E+V258P+A276S+N355G+A364G, and A25W+V45L+L149R+S214E+V258P+A276S+Q314A+A364G of SEQ ID NO: 1 and wherein said variant has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%, but less than 100% sequence identity to the polypeptide of SEQ ID NO: 1.
[0225] In one aspect, a variant comprises substitutions at positions corresponding to positions selected from a group consisting of: V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388R+D470T, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388L+D470T, V45L+A117S+L149R+S214Q+V258P+A276Q+A364G+S388K+D470T, V45L+A117S+L149R+D192E+S214Q+V258P+A276S+H358D+A364G, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388A+D470T, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388H+D470T, V45N+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T, V45L+A117S+L149R+S214E+V258P+A276S+H358D+A364G+S388K, V45L+A117S+L149R+D192E+S214Q+V258P+A276S+H358D+A364G, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+R483V, V45L+A117S+L149R+S214E+V258P+A276S+A364G+S388K+D470T, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388R, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388A, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+Q384A+S388K, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388L, V45L+A117S+L149R+S214Q+V258P+A276S+A286E+A364G+S388K, V45L+A117S+L149R+S214Q+V258P+A276S+L281V+A364G+S388K, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+G394D, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+S473G, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+G394A, V45N+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+L478P, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+S481A, V45L+A117S+L149R+S214Q+V258P+A276S+Q314A+A364G+S388K, V45L+A117S+L149R+S214Q+V258P+A276Q+H358D+A364G+S388K, V45L+A117S+L149R+G187K+S214Q+V258P+A276S+A364G+S388K, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+L478N, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+V393R, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+T366V+S388K, V45L+A117S+L149R+S214Q+V258P+A276S+H358T+A364G+S388K, D11E+V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+G394Q, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+N395D, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+V393H, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+S501E, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+S528H, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388H, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+S389H, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+T366I+S388K, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+N474G, V45L+A117S+L149R+S214Y+V258P+A276S+H358D+A364G+S388K, V45L+A117S+L149R+S214Q+V258P+A276S+A286S+A364G+S388K, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+A499Y, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+V500V, V45L+A117S+L149R+S214Q+W250Y+V258P+A276S+A364G+S388K, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+T480N, V45L+A117S+L149R+G187S+S214Q+V258P+A276S+A364G+S388K, A25W+V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+N476N, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+N476D, D9E+V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+S481S, V45L+A117S+L149R+S214Q+H219V+V258P+A276S+A364G+S388K, V45L+A117S+L149R+S214Q+T215I+V258P+A276S+A364G+S388K, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+Q496R, V45L+A117S+L149R+A170S+S214Q+V258P+A276S+A364G+S388K, V45L+Q61R+A117S+L149R+S214Q+V258P+A276S+A364G+S388K, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+V497P, V45L+A117S+L149R+T180Q+S214Q+V258P+A276S+A364G+S388K, V45L+A117S+L149R+S214Q+T215V+V258P+A276S+A364G+S388K, V45L+A117S+L149R+S214Q+V258P+A276S+V350L+A364G+S388K, V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+A364G+S388K, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+Y391V, V45L+A117S+L149R+N168G+S214Q+V258P+A276S+A364G+S388K, V45L+D113T+A117S+L149R+S214Q+V258P+A276S+A364G+S388K, M28P+V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+T477K, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+S389V, V45L+A117S+L149R+S173Y+S214Q+V258P+A276S+A364G+S388K, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+V500T, V45L+A117S+L149R+T211H+S214Q+V258P+A276S+A364G+S388K, V45L+S92D+A117S+L149R+S214Q+V258P+A276S+A364G+S388K, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+A472L, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+S473K, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+A499L, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+V498I, V45L+A117S+L149R+N163H+S214Q+V258P+A276S+A364G+S388K, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+N527H,V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+T477V, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+G503L, V45L+A117S+L149R+G187L+S214Q+V258P+A276S+A364G+S388K, V45L+A117S+L149R+S214Q+T215K+V258P+A276S+A364G+S388K, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+Q385C+S388K, and V45L+A117S+L149R+S214Q+V258P+A276S+N355G+A364G+S388K of SEQ ID NO: 1 and wherein said variant has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%, but less than 100% sequence identity to the polypeptide of SEQ ID NO: 1.
[0226] In one aspect, a variant comprises substitutions at positions corresponding to positions selected from a group consisting of: V45L+A117S+L149R+S214E+V258P+A276S+H358D+A364G+S388K+D470T, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388R+D470T, V45L+A117S+L149R+S214Q+V258P+A276Q+H358D+A364G+S388K+D470T, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388H+D470T, V45L+A79C+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388L+D470T, V45L+A117S+L149R+S214E+V258P+A276S+A364G+S388K+D470T+R483V, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388R+D470T+R483V, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470A+R483V, V45L+A117S+L149R+S214Q+V258P+A276Q+A364G+S388K+D470T+R483V, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T, V45N+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388H+D470T+R483V, V45L+A79C+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388A+D470T, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388A+D470T+R483V, V45L+A117S+L149R+S214Q+V258P+A276S+L281V+A364G+S388K+D470T, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+Q384A+S388K+D470T, V45L+A117S+L149R+S214Q+V258P+A276S+A286E+A364G+S388K+D470T, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+T477K, V45L+A117S+L149R+S214Y+V258P+A276S+H358D+A364G+S388K+D470T, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+G394A+D470T, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+N476D, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+V393H+D470T, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+N395D+D470T, V45L+A117S+L149R+S214Q+V258P+A276S+H358T+A364G+S388K+D470T, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+L478N, V45L+A117S+L149R+S214Q+W250Y+V258P+A276S+A364G+S388K+D470T, V45L+A117S+L149R+G187L+S214Q+V258P+A276S+A364G+S388K+D470T, D9E+V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T, V45L+A117S+L149R+S214Q+V258P+A276S+S282N+A364G+S388K+D470T, D11E+V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+N476N, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+G394D+D470T, V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T, V45L+A117S+L149R+S214Q+V258P+A276S+A286S+A364G+S388K+D470T, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470A, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+G394Q+D470T, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+L478P, V45L+A117S+L149R+S214Q+V258P+A276S+V350L+A364G+S388K+D470T, V45L+D113T+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T, V45L+A117S+L149R+T180Q+S214Q+V258P+A276S+A364G+S388K+D470T, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+S389H+D470T, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+V393R+D470T, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+Q496R, V45L+A117S+N127D+L149R+S214Q+V258P+A276S+A364G+S388K+D470T, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+A499Y, V45L+A117S+L149R+S173Y+S214Q+V258P+A276S+A364G+S388K+D470T, V45L+S92D+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+N529T, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+L478N, V45L+T70R+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T, M28P+V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T, V45L+A117S+L149R+S214Y+V258P+A276S+A364G+S388K+D470T+R483V, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+N395D, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+T477K, V45L+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K, V45L+Q61R+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T, V45L+A117S+L149R+S214Q+T215I+V258P+A276S+A364G+S388K+D470T, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+Q496E, V45L+A117S+L149R+G187K+S214Q+V258P+A276S+A364G+S388K+D470T, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+W495I, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+V498I, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+V500V, D11E+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K, V45L+A117S+L149R+A170S+S214Q+V258P+A276S+A364G+S388K+D470T, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+Y391V+D470T, V45L+A117S+L149R+S214Q+V258P+A276S+Q314A+A364G+S388K+D470T, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+T477V, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394Q, V45L+A117S+L149R+S214Q+H219V+V258P+A276S+A364G+S388K+D470T, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+Q496Q, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+A499Y, V45L+A117S+L149R+S214Q+T215V+V258P+A276S+A364G+S388K+D470T, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+Q385C+S388K+D470T, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+T480N, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+V497P, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+A499L, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+S501N, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+Q384A+S388K, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388L+D470T+R483V, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394A, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+V498I, V45L+A117S+L149R+S214Q+H219I+V258P+A276S+A364G+S388K+D470T, V45L+A117S+L149R+N163H+S214Q+V258P+A276S+A364G+S388K+D470T, V45L+A117S+L149R+S214Q+V258P+A276S+Q314A+H358D+A364G+S388K, V45L+A117S+L149R+S173Y+S214Q+V258P+A276S+H358D+A364G+S388K, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394D, V45L+Q61R+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+T366V+S388K, V45L+A117S+L149R+T180Q+S214Q+V258P+A276S+H358D+A364G+S388K, V45L+A117S+L149R+S214Q+T215I+V258P+A276S+H358D+A364G+S388K, V45L+A117S+L149R+S214Q+W250Y+V258P+A276S+H358D+A364G+S388K, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+N476D, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+T477V, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+L478P, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S481A, V45L+A117S+L149R+T211H+S214Q+V258P+A276S+A364G+S388K+D470T, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+V500T, V45L+A117S+L149R+S214Q+V258P+A276S+V350L+H358D+A364G+S388K, V45L+A117S+L149R+G187K+S214Q+V258P+A276S+H358D+A364G+S388K, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470V+R483V, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+V500V, V45L+A117S+L149R+N163H+S214Q+V258P+A276S+H358D+A364G+S388K, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S481S, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+V500T, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+W495S, V45L+D113T+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+N474G, V45L+A117S+L149R+S214Q+V258P+A276S+S282N+H358D+A364G+S388K, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+Q496Q, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+S389V+D470T, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S501E, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+N476N, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S473K, V45L+A117S+L149R+G187L+S214Q+V258P+A276S+H358D+A364G+S388K, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+Q496E, A25W+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K, V45L+A117S+L149R+N168G+S214Q+V258P+A276S+H358D+A364G+S388K, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S389H, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+T480L, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+Q385C+S388K, V45L+S92D+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K, V45L+A117S+L149R+A170S+S214Q+V258P+A276S+H358D+A364G+S388K, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+Y391V, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+T480N, D9E+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K, V45L+A117S+L149R+S214Q+H219I+V258P+A276S+H358D+A364G+S388K, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+A499L, V45L+A117S+L149R+S214Q+T215V+V258P+A276S+H358D+A364G+S388K, V45L+A117S+L149R+S214Q+H219V+V258P+A276S+H358D+A364G+S388K, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S389V, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+V393H, V45L+A117S+N127D+L149R+S214Q+V258P+A276S+H358D+A364G+S388K, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+A472L, V45L+A117S+L149R+T211H+S214Q+V258P+A276S+H358D+A364G+S388K, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+T480L, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+V393R, V45L+A117S+L149R+S214Q+V258P+A276S+A286S+H358D+A364G+S388K, V45L+A117S+L149R+S214Q+V258P+A276S+N355G+H358D+A364G+S388K, V45L+A117S+L149R+S214Q+V258P+A276S+N355G+A364G+S388K+D470T, V45L+A117S+L149R+S214Q+V258P+A276S+A286E+H358D+A364G+S388K, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+Y386G+S388K, and V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+S501E of SEQ ID NO: 1 and wherein said variant has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%, but less than 100% sequence identity to the polypeptide of SEQ ID NO: 1.
[0227] In one aspect, a variant comprises substitutions at positions corresponding to positions selected from a group consisting of: V45L+A79C+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V, V45L+A79C+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T, V45L+A117S+L149R+S214E+V258P+A276S+H358D+A364G+S388K+D470T+R483V, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V, V45L+A117S+L149R+S214E+V258P+A276S+H358D+A364G+S388K+D470T+L530R, V45L+A117S+L149R+S214Q+V258P+A276Q+H358D+A364G+S388K+D470T+R483V, V45L+A117S+L149R+S214Q+V258P+A276Q+H358D+A364G+S388K+D470T+L530R, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470A+R483V, V45N+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388H+D470T+L530R, V45N+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388A+D470T+L530R, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388A+D470T+R483V, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388L+D470T+R483V, V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+G394A+D470T+R483V, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L478N, V45L+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+D470T, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+T366I+S388K+D470T, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S473G, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L478P, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394D+D470T, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+Q384A+S388K+D470T+R483V, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N529T, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394Q+D470T, V45L+A117S+L149R+G187L+S214Q+V258P+A276S+H358D+A364G+S388K+D470T, V45L+A117S+L149R+S214Q+V258P+A276S+Q314A+H358D+A364G+S388K+D470T, V45L+A117S+L149R+S214Q+V258P+A276S+V350L+H358D+A364G+S388K+D470T, V45L+A117S+L149R+G187K+S214Q+V258P+A276S+H358D+A364G+S388K+D470T, V45L+A117S+L149R+S214Q+W250Y+V258P+A276S+H358D+A364G+S388K+D470T, V45L+A117S+L149R+S214Q+V258P+A276S+A286E+H358D+A364G+S388K+D470T, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+Q384A+S388K+D470T, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S528H, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+Q496R, V45L+A117S+L149R+N163H+S214Q+V258P+A276S+H358D+A364G+S388K+D470T, V45L+A117S+L149R+S214Q+V258P+A276S+S282N+H358D+A364G+S388K+D470T, D11E+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+T366V+S388K+D470T, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S473K, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388R+D470T+R483V, V45L+A117S+L149R+S214Q+V258P+A276S+Q314A+A364G+S388K+D470T+R483V, V45L+S92D+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T, V45L+A117S+L149R+S214Q+V258P+N260H+A276S+H358D+A364G+S388K+D470T, V45L+A117S+L149R+G187S+S214Q+V258P+A276S+H358D+A364G+S388K+D470T, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T477K, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N474G, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+N395D+D470T, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S501N, V45L+A117S+N127D+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+V393R+D470T, V45L+A117S+L149R+S173Y+S214Q+V258P+A276S+H358D+A364G+S388K+D470T, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T480N, V45L+A117S+L149R+N168G+S214Q+V258P+A276S+H358D+A364G+S388K+D470T, V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V, V45L+D113T+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+T366V+S388K+D470T+R483V, V45L+A117S+L149R+S214Q+V258P+A276S+H358T+A364G+S388K+D470T+R483V, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+V393R+D470T+R483V, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+Q496Q, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+G394Q+D470T+R483V, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+T366I+S388K+D470T+R483V, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L484S, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+A499L, V45L+A117S+L149R+S214Q+V258P+A276S+H358T+A364G+S388K+D470T+L530R, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+V498I, V45L+T70R+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+N476D+R483V, D9E+V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S501E, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S481A, V45L+A117S+L149R+S214Q+H219V+V258P+A276S+H358D+A364G+S388K+D470T, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S481S, V45L+A117S+L149R+G187K+S214Q+V258P+A276S+A364G+S388K+D470T+R483V, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+N395D+D470T+R483V, V45L+A117S+L149R+G187L+S214Q+V258P+A276S+A364G+S388K+D470T+R483V, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+V497P, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N527H, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+Q496Q, V45L+A117S+L149R+N168G+S214Q+V258P+A276S+A364G+S388K+D470T+R483V, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+N476N+R483V, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+T477V+R483V, V45L+A117S+L149R+S214Q+V258P+A276S+V350L+A364G+S388K+D470T+R483V, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+L478N+R483V, M28P+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+V393H+D470T+R483V, V45L+Q61R+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+V497P, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+V498I, V45L+A117S+L149R+S214Q+V258P+A276S+A286E+A364G+S388K+D470T+R483V, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+T477K+R483V, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+Q496E, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+Q496R, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+A499L, V45L+A117S+L149R+S214Q+T215I+V258P+A276S+H358D+A364G+S388K+D470T, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+Y391V+D470T+R483V, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N476D, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+V393H+D470T, V45L+A117S+L149R+S214Q+V258P+A276S+A286S+A364G+S388K+D470T+R483V, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+S501E, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+N529T, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+S501N, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+S481S+R483V, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+L478P+R483V, D11E+V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T477V, V45L+A117S+L149R+T211H+S214Q+V258P+A276S+H358D+A364G+S388K+D470T, V45L+A117S+L149R+S214Y+V258P+A276S+H358D+A364G+S388K+D470T+R483V, V45L+A117S+L149R+S214Q+W250Y+V258P+A276S+A364G+S388K+D470T+R483V, V45L+S92D+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+N527H, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+Q385C+S388K+D470T, V45L+A117S+L149R+S173Y+S214Q+V258P+A276S+A364G+S388K+D470T+R483V, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+S389H+D470T+R483V, V45L+A117S+L149R+S214Q+H219V+V258P+A276S+A364G+S388K+D470T+R483V, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+Q496E, V45L+A117S+L149R+A170S+S214Q+V258P+A276S+H358D+A364G+S388K+D470T, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S389V+D470T, V45L+T70R+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T, V45L+A117S+L149R+S214Q+H219I+V258P+A276S+A364G+S388K+D470T+R483V, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+A499Y, V45L+A117S+L149R+S214Q+V258P+A276S+L281V+A364G+S388K+D470T+R483V, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+V500T, V45L+A117S+L149R+T180Q+S214Q+V258P+A276S+H358D+A364G+S388K+D470T, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+V500V, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+G526T, V45L+A117S+L149R+S214Q+V258P+A276S+A286S+H358D+A364G+S388K+D470T, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470A+L530R, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+D525L, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N476N, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S389H+D470T, V45L+A117S+L149R+S214Y+V258P+A276S+H358D+A364G+S388K+D470T+L530R, A25W+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T, V45L+A117S+L149R+S214Q+T215V+V258P+A276S+A364G+S388K+D470T+R483V, V45L+Q61R+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T, V45L+A117S+L149R+S214Q+H219I+V258P+A276S+H358D+A364G+S388K+D470T, V45L+A117S+L149R+T211H+S214Q+V258P+A276S+A364G+S388K+D470T+R483V, V45L+D95N+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S473G, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+G503L, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+D525L, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+V500T, V45L+A117S+L149R+S214Q+T215V+V258P+A276S+H358D+A364G+S388K+D470T, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T480L, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+S389V+D470T+R483V, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+V497E, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470V+R483V, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470K+R483V, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+A472L, V45L+D113T+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V, V45L+A117S+L149R+S214Q+T215K+V258P+A276S+A364G+S388K+D470T+R483V, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+V497W, V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+W495E, V45L+A117S+L149R+S214Q+T215K+V258P+A276S+H358D+A364G+S388K+D470T, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388H+D470T+R483V, and V45L+A117S+L149R+S214Q+V258P+A276S+N355G+H358D+A364G+S388K+D470T of SEQ ID NO: 1 and wherein said variant has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%, but less than 100% sequence identity to the polypeptide of SEQ ID NO: 1.
[0228] In one aspect, a variant comprises substitutions at positions corresponding to positions selected from a group consisting of: V45L+A79C+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R, V45L+A79C+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+Q385C+S388K+D470T+R483V, V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V, V45L+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+D470T+R483V, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+T366I+S388K+D470T+R483V, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+Q384A+S388K+D470T+L530R, V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R, V45L+T70R+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+V393H+D470T+R483V, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394A+D470T+R483V, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+V393H+D470T+L530R, V45L+A117S+L149R+S214Q+V258P+A276S+A286E+H358D+A364G+S388K+D470T+R483V+D11E+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V, V45L+A117S+L149R+G187L+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+Q384A+S388K+D470T+R483V, V45L+A117S+L149R+G187K+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V, V45L+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+D470T+L530R, V45L+A117S+L149R+G187L+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394Q+D470T+R483V, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394A+D470T+L530R, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+T366V+S388K+D470T+L530R, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394Q+D470T+L530R, V45L+A117S+L149R+S214Q+V258P+A276S+S282N+H358D+A364G+S388K+D470T+R483V, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+N395D+D470T+R483V, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N476D+R483V, V45L+A117S+L149R+S214Q+V258P+A276S+V350L+H358D+A364G+S388K+D470T+R483V, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T477K+R483V, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+Q496R, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+W495E, V45L+A117S+L149R+S214Q+V258P+A276S+A286E+H358D+A364G+S388K+D470T+L530R, V45L+A117S+L149R+G187K+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+Y391V+D470T+R483V, D9E+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T477V+R483V, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N476N+R483V, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+V393R+D470T+R483V, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T480L+L530R, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S481A+L530R, V45L+A117S+L149R+S214Q+W250Y+V258P+A276S+H358D+A364G+S388K+D470T+R483V, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S481S+R483V, V45L+A117S+L149R+S173Y+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V, V45L+A117S+L149R+T180Q+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R, D11E+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N476D+L530R, V45L+A117S+L149R+S214Q+V258P+A276S+A286S+H358D+A364G+S388K+D470T+R483V, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+Q496Q, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+Q496E, V45L+Q61R+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R, V45L+A117S+L149R+S214Q+V258P+A276S+Q314A+H358D+A364G+S388K+D470T+L530R, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L478P+R483V, A25W+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V, V45L+A117S+L149R+T180Q+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+L484K, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N474G+L530R, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+N395D+D470T+L530R, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+T366V+S388K+D470T+R483V, V45L+A117S+L149R+N168G+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+L484S, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+L484D, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+S528H, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+S501N, V45L+A117S+L149R+S173Y+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+A499L, V45L+S92D+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V, V45L+A117S+L149R+S214Q+V258P+A276S+Q314A+H358D+A364G+S388K+D470T+R483V, V45L+A117S+L149R+S214Q+V258P+A276S+N355G+H358D+A364G+S388K+D470T+L530R, V45L+A117S+L149R+S214Q+V258P+A276S+V350L+H358D+A364G+S388K+D470T+L530R, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S481S+L530R, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+Q496E+L530R, V45L+A117S+L149R+N168G+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+V498I+L530R, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+A499Y, V45L+A117S+L149R+S214Q+V258P+A276S+A286S+H358D+A364G+S388K+D470T+L530R, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S501N+L530R, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N476N+L530R, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T477V+L530R, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L478N+L530R, V45L+S92D+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+V500V+L530R, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+V500V, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L478P+L530R, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+S501E, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+D525L+L530R, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+G526T+L530R, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N527H+L530R, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T477K+L530R, M28P+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R, D9E+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S501E+L530R, V45L+A117S+L149R+S214Q+W250Y+V258P+A276S+H358D+A364G+S388K+D470T+L530R, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+A499L+L530R, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+A472I+L530R, V45L+A117S+N127D+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+V500T+L530R, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+N527H, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T480N+L530R, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+V497P, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+V498I, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T480N+R483V, V45L+A117S+L149R+S214Q+H219V+V258P+A276S+H358D+A364G+S388K+D470T+L530R, M28P+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V, V45L+A117S+L149R+A170S+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S389H+D470T+L530R, V45L+D113T+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R, V45L+A117S+L149R+N163H+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V, V45L+A117S+L149R+T211H+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+V500T, V45L+D113T+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V, V45L+D95N+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394A+D470T, V45L+A93T+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+A499Y, V45L+A117S+L149R+S214Q+T215I+V258P+A276S+H358D+A364G+S388K+D470T+R483V, V45L+A117S+L149R+S214Q+H219I+V258P+A276S+H358D+A364G+S388K+D470T+R483V, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+Q385C+S388K+D470T+L530R, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+L530R, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+G503L, V45L+A117S+L149R+S214Q+T215V+V258P+A276S+H358D+A364G+S388K+D470T+R483V, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S481A+R483V, V45L+A117S+L149R+S214Q+T215V+V258P+A276S+H358D+A364G+S388K+D470T+L530R, V45L+A117S+L149R+G187S+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R, V45L+A117S+L149R+T211H+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+G526T, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+D525L, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S528H+L530R, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+I469T+D470T+R483V, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N529T+L530R, V45L+A117S+L149R+S214Q+V258P+A276S+S282N+H358D+A364G+S388K+D470T+L530R, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+G503L+L530R, V45L+A117S+L149R+S214Q+H219I+V258P+A276S+H358D+A364G+S388K+D470T+L530R, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+V497P+L530R, V45L+A117S+L149R+S214Q+T215I+V258P+A276S+H358D+A364G+S388K+D470T+L530R, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S389V+D470T+R483V, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S389V+D470T+L530R, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+V497D, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L478N+R483V, V45L+T70R+D95N+A117S+L149R+S214Q+V258P+A276S+L356M+H358D+A364G+S388K, V45L+A117S+L149R+S214Q+T215K+V258P+A276S+H358D+A364G+S388K+D470T+R483V, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+V497W, V45L+T70R+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R, V45L+A117S+L149R+S214Q+T215K+V258P+A276S+H358D+A364G+S388K+D470T+L530R, V45L+Q61R+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V, V45L+A117S+L149R+S214Q+V258P+A276S+N355G+H358D+A364G+S388K+D470T+R483V, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+V497E, V45L+A117S+L149R+N163H+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+Y386G+S388K+D470T+R483V, and V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394D+D470T+R483V of SEQ ID NO: 1 and wherein said variant has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%, but less than 100% sequence identity to the polypeptide of SEQ ID NO: 1.
[0229] In one aspect, a variant comprises substitutions at positions corresponding to positions selected from a group consisting of: V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V, V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V, V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V, V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V, V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V, V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V, V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V, V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V, V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V, V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V, V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+L530R, V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+D470T+R483V+L530R, V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+D470T+R483V+L530R, and V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V of SEQ ID NO: 1 and wherein said variant has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%, but less than 100% sequence identity to the polypeptide of SEQ ID NO: 1.
[0230] In one aspect, a variant comprises substitutions at positions corresponding to positions selected from a group consisting of: V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V+L530R, V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V+L530R, V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V+L530R, V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V+L530R, V45L+A117S+L149R+G187K+S214Q+V258P+A276S+A286E+H358D+A364G+Q384A+S388K+V393H+D470T+R483V, V45L+A117S+L149R+G187K+S214Q+V258P+A276S+A286E+H358D+A364G+Q384A+S388K+N395D+D470T+R483V, V45L+A117S+L149R+G187K+S214E+T215I+V258P+A276S+A286E+H358D+A364G+S388K+V393H+D470T+R483V, V45L+A117S+L149R+G187K+S214E+T215I+V258P+A276S+A286E+H358D+A364G+S388K+N395D+D470T+R483V, V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+C468V+D470T+R483V, V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+C468A+D470T+R483V, V45L+T70R+A117S+L149R+S214Q+C243V+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V, V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+C468L+D470T+R483V, V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+C375V+S388K+G394A+D470T+R483V, V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+C468S+D470T+R483V, V45L+C60L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V, V45L+C69L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V, V45L+C60A+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V, V45L+T70R+A117S+L149R+S214Q+C243L+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V, V45L+C60S+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V, V45L+C69A+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V, V45L+T70R+A117S+L149R+C161S+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V, V45L+C69V+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V, V45L+C60V+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V, V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+C375A+S388K+G394A+D470T+R483V, V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+C375S+S388K+G394A+D470T+R483V, V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V+C540A, V45L+C69S+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V, V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+C375L+S388K+G394A+D470T+R483V, V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V+C540L, V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V+C522S, V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V+C540S, V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+C396S+D470T+R483V, V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+C396A+D470T+R483V, C40L, V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V, C40A, V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V+C40S, V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V, C40V, V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V, V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+C396V+D470T+R483V, V45L+T70R+A117S+L149R+C161V+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V, V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+C396L+D470T+R483V, V45L+T70R+A117S+L149R+C161L+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V, V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V+C522A, V45L+T70R+A117S+L149R+S214Q+C243S+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V, V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V+C522V, and V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V+C540V of SEQ ID NO: 1 and wherein said variant has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%, but less than 100% sequence identity to the polypeptide of SEQ ID NO: 1.
[0231] In one aspect, a variant comprises substitutions at positions corresponding to positions selected from a group consisting of: V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q384A+S388K+G394Q+D470T+R483V, V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q384A+S388K+G394A+D470T+R483V, V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q384A+S388K+V393H+D470T+R483V, V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q384A+S388K+V393H+D470T+R483V, V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q384A+S388K+G394A+D470T+R483V, V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q384A+S388K+V393H+D470T+R483V, V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q384A+S388K+G394A+D470T+R483V, V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q384A+S388K+V393H+D470T+R483V, and V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q384A+S388K+G394A+D470T+R483V of SEQ ID NO: 1 and wherein said variant has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%, but less than 100% sequence identity to the polypeptide of SEQ ID NO: 1.
[0232] In one aspect, a variant comprises substitutions at positions corresponding to positions selected from a group consisting of: V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+A286E+H358D+A364G+Q384A+S388K+V393H+D470T+R483V, and V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+A286E+H358D+A364G+Q384A+S388K+V393H+D470T+R483V of SEQ ID NO: 1 and wherein said variant has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%, but less than 100% sequence identity to the polypeptide of SEQ ID NO: 1.
[0233] In one aspect, the xylanase variants of the present invention have an improved property relative to the parent polypeptide, wherein the improved property is selected from the group consisting of increased catalytic efficiency, increased catalytic rate, increased chemical stability, increased oxidation stability, increased pH activity, increased pH stability, increased specific activity, increased stability under storage conditions, increased substrate binding, increased substrate cleavage, increased substrate specificity, increased substrate stability, increased surface properties, increased thermal activity, and increased thermostability.
[0234] In one aspect, the xylanase variants of the present invention have improved property relative to said parent polypeptide.
[0235] In one aspect, the xylanase variants of the present invention have improved property relative to said parent polypeptide and wherein said improved property is increased thermostability.
[0236] In one aspect, the xylanase variant has improved (increased) thermostability relative to the parent xylanase.
[0237] In one aspect, the xylanase variant has improved (increased) thermostability relative to SEQ ID NO: 1.
[0238] In one aspect, the xylanase variant has increased thermostability measured as increased melting temperature using TSA.
[0239] In one aspect, the xylanase variant has increased thermostability measured as increased melting temperature using TSA relative to SEQ ID NO: 1 of at least 1° C., at least 1.5° C., at least 2° C., at least 2.5° C., at least 3° C., at least 3.5° C., at least 4.0° C., at least 4.5° C. or at least 5° C.
[0240] In one aspect, the xylanase variant has increased thermostability measured as increased melting temperature using n-DSF.
[0241] In one aspect, the xylanase variant has increased thermostability measured as increased melting temperature using n-DSF relative to SEQ ID NO: 1 of at least 1° C., at least 1.5° C., at least 2° C., at least 2.5° C., at least 3° C., at least 3.5° C., at least 4.0° C., at least 4.5° C. or at least 5° C.
[0242] In one aspect, the present invention relates to xylanase variants comprises at least one of the following substitutions or combinations of substitutions:
[0243] V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+A286E+H358D+A364G+Q384A+S388K+V393H+D470T+R483V;
[0244] V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q384A+S388K+G394Q+D470T+R483V;
[0245] V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q384A+S388K+G394A+D470T+R483V;
[0246] V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q384A+S388K+V393H+D470T+R483V;
[0247] V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q384A+S388K+V393H+D470T+R483V;
[0248] V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q384A+S388K+G394A+D470T+R483V;
[0249] V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q384A+S388K+V393H+D470T+R483V;
[0250] V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q384A+S388K+G394A+D470T+R483V;
[0251] V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+A286E+H358D+A364G+Q384A+S388K+V393H+D470T+R483V;
[0252] V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q384A+S388K+V393H+D470T+R483V;
[0253] V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q384A+S388K+G394A+D470T+R483V;
[0254] V45L+A79C+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[0255] V45L+A79C+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[0256] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[0257] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[0258] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[0259] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[0260] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[0261] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[0262] V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V+L530R;
[0263] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[0264] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[0265] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[0266] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[0267] V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+L530R;
[0268] V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V+L530R;
[0269] V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V+L530R;
[0270] V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+D470T+R483V+L530R;
[0271] V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V+L530R;
[0272] V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+D470T+R483V+L530R;
[0273] V45L+A117S+L149R+G187K+S214Q+V258P+A276S+A286E+H358D+A364G+Q384A+S388K+V393H+D470T+R483V;
[0274] V45L+A117S+L149R+G187K+S214Q+V258P+A276S+A286E+H358D+A364G+Q384A+S388K+N395D+D470T+R483V;
[0275] V45L+A117S+L149R+G187K+S214E+T215I+V258P+A276S+A286E+H358D+A364G+S388K+V393H+D470T+R483V;
[0276] V45L+A117S+L149R+G187K+S214E+T215I+V258P+A276S+A286E+H358D+A364G+S388K+N395D+D470T+R483V;
[0277] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+Q385C+S388K+D470T+R483V;
[0278] V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[0279] V45L+A79C+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V;
[0280] V45L+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+D470T+R483V;
[0281] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+T366I+S388K+D470T+R483V;
[0282] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[0283] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+Q384A+S388K+D470T+L530R;
[0284] V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[0285] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[0286] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+V393H+D470T+R483V;
[0287] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394A+D470T+R483V;
[0288] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+V393H+D470T+L530R;
[0289] V45L+A117S+L149R+S214Q+V258P+A276S+A286E+H358D+A364G+S388K+D470T+R483V; D11E+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[0290] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+C468V+D470T+R483V;
[0291] V45L+A79C+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T V45L+A79C+L149R+S214E+V258P+A276S+A364G+S388K;
[0292] V45L+A117S+L149R+G187L+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[0293] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+Q384A+S388K+D470T+R483V;
[0294] V45L+A117S+L149R+G187K+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[0295] V45L+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+D470T+L530R;
[0296] V45L+A117S+L149R+S214E+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[0297] V45L+A117S+L149R+G187L+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[0298] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394Q+D470T+R483V;
[0299] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394A+D470T+L530R;
[0300] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+T366V+S388K+D470T+L530R;
[0301] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394Q+D470T+L530R;
[0302] V45L+A117S+L149R+S214Q+V258P+A276S+S282N+H358D+A364G+S388K+D470T+R483V;
[0303] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+N395D+D470T+R483V;
[0304] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N476D+R483V;
[0305] V45L+A117S+L149R+S214Q+V258P+A276S+V350L+H358D+A364G+S388K+D470T+R483V;
[0306] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T477K+R483V;
[0307] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+Q496R;
[0308] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+C468A+D470T+R483V;
[0309] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+W495E;
[0310] V45L+A117S+L149R+S214Q+V258P+A276S+A286E+H358D+A364G+S388K+D470T+L530R;
[0311] V45L+A117S+L149R+G187K+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[0312] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+Y391V+D470T+R483V;
[0313] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V; D9E+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[0314] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T477V+R483V;
[0315] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N476N+R483V;
[0316] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+V393R+D470T+R483V;
[0317] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T480L+L530R;
[0318] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S481A+L530R;
[0319] V45L+A117S+L149R+S214Q+W250Y+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[0320] V45L+A117S+L149R+S214Q+V258P+H358D+A364G+S388K+D470T+S481S+R483V;
[0321] V45L+A117S+L149R+S173Y+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[0322] V45L+T70R+A117S+L149R+S214Q+C243V+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[0323] V45L+A117S+L149R+T180Q+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R; D11E+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[0324] V45L+A117S+L149R+S214E+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[0325] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N476D+L530R;
[0326] V45L+A117S+L149R+S214Q+V258P+A276S+A286S+H358D+A364G+S388K+D470T+R483V;
[0327] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+Q496Q;
[0328] V45L+A117S+L149R+S214Q+V258P+A276Q+H358D+A364G+S388K+D470T+R483V;
[0329] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+Q496E;
[0330] V45L+Q61R+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[0331] V45L+A117S+L149R+S214Q+V258P+A276S+Q314A+H358D+A364G+S388K+D470T+L530R;
[0332] V45L+A117S+L149R+S214Q+V258P+A276Q+H358D+A364G+S388K+D470T+L530R;
[0333] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L478P+R483V; A25W+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[0334] V45L+A117S+L149R+T180Q+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[0335] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+L484K
[0336] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N474G+L530R;
[0337] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+N395D+D470T+L530R;
[0338] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+T366V+S388K+D470T+R483V;
[0339] V45L+A117S+L149R+N168G+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[0340] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+L484S;
[0341] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[0342] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+L484D;
[0343] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+S528H;
[0344] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+S501N;
[0345] V45L+A117S+L149R+S173Y+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[0346] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+A499L;
[0347] V45L+S92D+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[0348] V45L+A117S+L149R+S214Q+V258P+A276S+Q314A+H358D+A364G+S388K+D470T+R483V;
[0349] V45L+A79C+L149R+S214Q+V258P+A276S+A364G+S388K;
[0350] V45L+A117S+L149R+S214Q+V258P+A276S+N355G+H358D+A364G+S388K+D470T+L530R;
[0351] V45L+A117S+L149R+S214Q+V258P+A276S+V350L+H358D+A364G+S388K+D470T+L530R;
[0352] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S481S+L530R;
[0353] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+Q496E+L530R;
[0354] V45L+A117S+L149R+N168G+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[0355] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+V498I+L530R;
[0356] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470A+R483V;
[0357] V45N+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[0358] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+A499Y;
[0359] V45L+A79C+L149R+V258P+A276S+Q314A+A364G+S388K;
[0360] V45L+A79C+L149R+V258P+A276S+L281V+A364G+S388K;
[0361] V45L+A117S+L149R+S214Q+V258P+A276S+A286S+H358D+A364G+S388K+D470T+L530R;
[0362] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S501N+L530R;
[0363] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N476N+L530R;
[0364] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T477V+L530R;
[0365] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388H+D470T+L530R;
[0366] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L478N+L530R;
[0367] V45L+S92D+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[0368] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+V500V+L530R;
[0369] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+V500V;
[0370] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L478P+L530R;
[0371] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+S501E;
[0372] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+D525L+L530R;
[0373] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+G526T+L530R;
[0374] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N527H+L530R;
[0375] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T477K+L530R; M28P+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R; D9E+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[0376] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S501E+L530R;
[0377] V45L+A117S+L149R+S214Q+W250Y+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[0378] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+A499L+L530R;
[0379] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+A472I+L530R;
[0380] V45L+A117S+N127D+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[0381] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+V500T+L530R;
[0382] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+N527H;
[0383] V45N+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[0384] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T480N+L530R;
[0385] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+V497P;
[0386] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+V498I;
[0387] V45L+A79C+L149R+S173Y+V258P+A276S+A364G+S388K;
[0388] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T480N+R483V;
[0389] V45L+A117S+L149R+S214Q+H219V+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[0390] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388A+D470T+L530R;
[0391] M28P+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[0392] V45L+A117S+L149R+A170S+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[0393] V45L+A79C+L149R+G187K+V258P+A276S+A364G+S388K;
[0394] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S389H+D470T+L530R;
[0395] V45L+D113T+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[0396] V45L+A117S+L149R+N163H+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[0397] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388A+D470T+R483V;
[0398] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388L+D470T+R483V;
[0399] V45L+Q61R+A79C+L149R+V258P+A276S+A364G+S388K;
[0400] V45L+A79C+L149R+N168G+V258P+A276S+A364G+S388K;
[0401] V45L+A117S+L149R+T211H+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[0402] V45L+A79C+L149R+T215V+V258P+A276S+A364G+S388K;
[0403] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+V500T;
[0404] V45L+A79C+L149R+V258P+A276S+A286S+A364G+S388K;
[0405] V45L+A79C+L149R+H219V+V258P+A276S+A364G+S388K;
[0406] V45L+A79C+L149R+A170S+V258P+A276S+A364G+S388K;
[0407] V45L+D113T+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[0408] V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[0409] V45L+D95N+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394A+D470T;
[0410] V45L+A79C+L149R+V258P+A276S+A364G+S388K;
[0411] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+G394A+D470T+R483V;
[0412] V45L+A93T+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+A499Y;
[0413] V45L+A117S+L149R+S214Q+T215I+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[0414] V45L+A117S+L149R+S214Q+H219I+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[0415] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L478N;
[0416] V45L+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+D470T;
[0417] V45L+A117S+L149R+S214E+V258P+A276S+H358D+A364G+S388K+D470T;
[0418] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+C468L+D470T+R483V;
[0419] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+Q385C+S388K+D470T+L530R;
[0420] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+T366I+S388K+D470T;
[0421] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S473G;
[0422] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L478P;
[0423] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394D+D470T;
[0424] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+Q384A+S388K+D470T+R483V; D11E+V45L+A79C+L149R+V258P+A276S+A364G+S388K;
[0425] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+L530R;
[0426] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N529T;
[0427] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394Q+D470T;
[0428] V45L+A117S+L149R+G187L+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[0429] V45L+A79C+L149R+V258P+A276S+A286E+A364G+S388K;
[0430] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+G503L;
[0431] V45L+A117S+L149R+S214Q+V258P+A276S+Q314A+H358D+A364G+S388K+D470T;
[0432] V45L+A117S+L149R+S214Q+V258P+A276S+V350L+H358D+A364G+S388K+D470T;
[0433] V45L+A117S+L149R+G187K+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[0434] V45L+A117S+L149R+S214Q+W250Y+V258P+A276S+H358D+A364G+S388K+D470T;
[0435] V45L+A117S+L149R+S214Q+V258P+A276S+A286E+H358D+A364G+S388K+D470T;
[0436] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+Q384A+S388K+D470T;
[0437] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388R+D470T;
[0438] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S528H V45L+A117S+L149R+S214Q+T215V+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[0439] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+Q496R;
[0440] V45L+A117S+L149R+N163H+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[0441] V45L+A117S+L149R+S214Q+V258P+A276S+S282N+H358D+A364G+S388K+D470T;
[0442] V45L+A117S+L149R+S214Q+V258P+A276Q+H358D+A364G+S388K+D470T; D11E+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[0443] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+T366V+S388K+D470T;
[0444] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S473K;
[0445] V45L+A79C+L149R+T180Q+V258P+A276S+A364G+S388K;
[0446] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S481A+R483V;
[0447] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388R+D470T+R483V;
[0448] V45L+A117S+L149R+S214Q+V258P+A276S+Q314A+A364G+S388K+D470T+R483V;
[0449] V45L+S92D+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[0450] V45L+A117S+L149R+S214Q+V258P+N260H+A276S+H358D+A364G+S388K+D470T;
[0451] V45L+A117S+L149R+G187S+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[0452] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T477K;
[0453] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N474G;
[0454] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+N395D+D470T;
[0455] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S501N;
[0456] V45L+A117S+N127D+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[0457] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+V393R+D470T;
[0458] V45L+A117S+L149R+S173Y+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[0459] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388H+D470T;
[0460] V45L+A117S+L149R+S214Q+T215V+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[0461] V45L+A117S+L149R+G187S+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[0462] V45L+A117S+L149R+T211H+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[0463] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T480N;
[0464] V45L+A117S+L149R+N168G+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[0465] V45L+A79C+L149R+H219I+V258P+A276S+A364G+S388K;
[0466] V45L+L149R+S214E+V258P+A276S+H358D+A364G+D470T;
[0467] V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V;
[0468] V45L+D113T+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[0469] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+T366V+S388K+D470T+R483V;
[0470] V45L+A117S+L149R+S214Q+V258P+A276S+H358T+A364G+S388K+D470T+R483V;
[0471] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+V393R+D470T+R483V;
[0472] V45N+A79C+L149R+V258P+A276S+A364G+S388K;
[0473] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+Q496Q;
[0474] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+G394Q+D470T+R483V;
[0475] V45L+A79C+L149R+V258P+A276S+V350L+A364G+S388K;
[0476] V45L+L149R+S214E+V258P+A276S+H358D+A364G+D470T;
[0477] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+T366I+S388K+D470T+R483V;
[0478] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+G526T;
[0479] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L484S;
[0480] V45L+A79C+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K;
[0481] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+A499L;
[0482] V45L+A117S+L149R+S214Q+V258P+A276S+H358T+A364G+S388K+D470T+L530R;
[0483] V45L+A79C+D113T+L149R+V258P+A276S+A364G+S388K;
[0484] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+D525L;
[0485] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+V498I;
[0486] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388L+D470T;
[0487] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V;
[0488] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S528H+L530R;
[0489] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+N476D+R483V; D9E+V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+S501E;
[0490] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S481A;
[0491] V45L+A117S+L149R+S214Q+H219V+V258P+A276S+H358D+A364G+S388K+D470T;
[0492] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S481S;
[0493] V45L+A117S+L149R+G187K+S214Q+V258P+A276S+A364G+S388K+D470T+R483V;
[0494] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+N395D+D470T+R483V;
[0495] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+I469T+D470T+R483V;
[0496] V45L+A79C+N127D+L149R+V258P+A276S+A364G+S388K; D9E+V45L+A79C+L149R+V258P+A276S+A364G+S388K;
[0497] V45L+L149R+S214E+V258P+A276S+H358D+A364G+D470T;
[0498] V45L+A117S+L149R+G187L+S214Q+V258P+A276S+A364G+S388K+D470T+R483V;
[0499] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N529T+L530R;
[0500] V45L+A79C+L149R+W250Y+V258P+A276S+A364G+S388K;
[0501] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+V497P;
[0502] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N527H;
[0503] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+Q496Q;
[0504] V45L+A117S+L149R+N168G+S214Q+V258P+A276S+A364G+S388K+D470T+R483V;
[0505] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+N476N+R483V;
[0506] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+T477V+R483V;
[0507] V45L+A117S+L149R+S214Q+V258P+A276S+V350L+A364G+S388K+D470T+R483V;
[0508] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+L478N+R483V;
[0509] V45L+A117S+L149R+S214E+V258P+A276S+A364G+S388K+D470T+R483V; M28P+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[0510] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+V393H+D470T+R483V;
[0511] V45L+Q61R+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V;
[0512] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+V497P;
[0513] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+V498I;
[0514] V45L+A117S+L149R+S214Q+V258P+A276S+S282N+H358D+A364G+S388K+D470T+L530R;
[0515] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+C375V+S388K+G394A+D470T+R483V;
[0516] V45L+A117S+L149R+S214Q+V258P+A276S+A286E+A364G+S388K+D470T+R483V;
[0517] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388R+D470T+R483V;
[0518] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470A+R483V;
[0519] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+T477K+R483V;
[0520] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+Q496E;
[0521] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+Q496R;
[0522] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+A499L;
[0523] V45L+L149R+S214E+V258P+A276S+H358D+A364G+D470T;
[0524] V45L+L149R+S214E+V258P+A276S+H358D+A364G+D470T;
[0525] V45L+A117S+L149R+S214Q+T215I+V258P+A276S+H358D+A364G+S388K+D470T;
[0526] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+C468S+D470T+R483V;
[0527] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+Y391V+D470T+R483V:
[0528] V45L+A117S+L149R+S214Q+V258P+A276Q+A364G+S388K+D470T+R483V;
[0529] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+G503L+L530R;
[0530] V45L+A117S+L149R+S214Q+H219I+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[0531] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N476D;
[0532] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+V393H+D470T;
[0533] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V;
[0534] V45L+A117S+L149R+S214Q+V258P+A276S+A286S+A364G+S388K+D470T+R483V;
[0535] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+S501E;
[0536] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+N529T;
[0537] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+S501N;
[0538] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[0539] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+S481S+R483V;
[0540] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+L478P+R483V; D11E+V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V;
[0541] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T477V;
[0542] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+V497P+L530R;
[0543] V45L+A117S+L149R+T211H+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[0544] V45L+A117S+L149R+S214Y+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[0545] V45L+A117S+L149R+S214Q+W250Y+V258P+A276S+A364G+S388K+D470T+R483V;
[0546] V45L+S92D+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V;
[0547] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+N527H;
[0548] V45N+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V;
[0549] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+Q385C+S388K+D470T;
[0550] V45L+A117S+L149R+S173Y+S214Q+V258P+A276S+A364G+S388K+D470T+R483V;
[0551] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388H+D470T+R483V;
[0552] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+S389H+D470T+R483V;
[0553] V45L+A117S+L149R+S214Q+H219V+V258P+A276S+A364G+S388K+D470T+R483V;
[0554] V45L+A79C+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T;
[0555] V45L+A117S+L149R+S214Q+T215I+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[0556] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+Q496E;
[0557] V45L+A117S+L149R+A170S+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[0558] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S389V+D470T+R483V;
[0559] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S389V+D470T+L530R;
[0560] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388A+D470T;
[0561] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S389V+D470T;
[0562] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[0563] V45L+A117S+L149R+S214Q+H219I+V258P+A276S+A364G+S388K+D470T+R483V;
[0564] V45L+A79C+L149R+N163H+V258P+A276S+A364G+S388K;
[0565] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+A499Y;
[0566] V45L+A117S+L149R+S214Q+V258P+A276S+L281V+A364G+S388K+D470T+R483V;
[0567] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+V500T;
[0568] V45L+A117S+L149R+T180Q+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[0569] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+V500V;
[0570] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+G526T;
[0571] V45L+C60L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[0572] V45L+C69L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[0573] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388A+D470T+R483V;
[0574] V45L+A117S+L149R+S214Q+V258P+A276S+A286S+H358D+A364G+S388K+D470T;
[0575] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+V497D;
[0576] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470A+L530R;
[0577] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+D525L;
[0578] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N476N;
[0579] V45L+A117S+L149R+S214Q+V258P+A276S+L281V+A364G+S388K+D470T;
[0580] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+Q384A+S388K+D470T;
[0581] V45L+A117S+L149R+S214Q+V258P+A276S+A286E+A364G+S388K+D470T;
[0582] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+T477K;
[0583] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S389H+D470T;
[0584] V45L+A117S+L149R+S214Y+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[0585] V45L+A117S+L149R+S214Y+V258P+A276S+H358D+A364G+S388K+D470T;
[0586] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+G394A+D470T;
[0587] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+N476D;
[0588] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L478N+R483V;
[0589] V45L+C60A+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[0590] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+V393H+D470T;
[0591] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+N395D+D470T; A25W+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[0592] V45L+T70R+A117S+L149R+S214Q+C243L+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[0593] V45L+A117S+L149R+S214Q+V258P+A276S+H358T+A364G+S388K+D470T;
[0594] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+L478N;
[0595] V45L+C60S+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[0596] V45L+A117S+L149R+S214Q+W250Y+V258P+A276S+A364G+S388K+D470T;
[0597] V45L+A117S+L149R+S214Q+T215V+V258P+A276S+A364G+S388K+D470T+R483V;
[0598] V45L+Q61R+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[0599] V45L+A117S+L149R+G187L+S214Q+V258P+A276S+A364G+S388K+D470T; D9E+V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T;
[0600] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G;
[0601] V45L+C69A+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[0602] V45L+T70R+A117S+L149R+C161S+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[0603] V45L+A117S+L149R+S214Q+H219I+V258P+A276S+H358D+A364G+S388K+D470T;
[0604] V45L+A117S+L149R+S214Q+V258P+A276S+S282N+A364G+S388K+D470T;
[0605] V45L+A117S+L149R+T211H+S214Q+V258P+A276S+A364G+S388K+D470T+R483V;
[0606] V45L+D95N+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S473G;
[0607] V45L+T70R+D95N+A117S+L149R+S214Q+V258P+A276S+L356M+H358D+A364G+S388K; D11E+V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T;
[0608] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+N476N;
[0609] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+G394D+D470T;
[0610] V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T;
[0611] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+G503L;
[0612] V45L+A117S+L149R+S214Q+V258P+A276S+A286S+A364G+S388K+D470T;
[0613] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470A;
[0614] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+G394Q+D470T;
[0615] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388R+D470T;
[0616] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+L478P;
[0617] V45L+A117S+L149R+S214Q+V258P+A276S+V350L+A364G+S388K+D470T;
[0618] V45L+D113T+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T;
[0619] V45L+A117S+L149R+T180Q+S214Q+V258P+A276S+A364G+S388K+D470T;
[0620] V45L+C69V+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[0621] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+D525L;
[0622] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T;
[0623] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+V500T;
[0624] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+S389H+D470T;
[0625] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+V393R+D470T;
[0626] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+Q496R;
[0627] V45L+A117S+N127D+L149R+S214Q+V258P+A276S+A364G+S388K+D470T;
[0628] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+A499Y;
[0629] V45L+A117S+L149R+S214Q+T215V+V258P+A276S+H358D+A364G+S388K+D470T;
[0630] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T480L;
[0631] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388L+D470T;
[0632] V45L+A117S+L149R+S173Y+S214Q+V258P+A276S+A364G+S388K+D470T;
[0633] V45L+S92D+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T;
[0634] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+S389V+D470T+R483V;
[0635] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+N529T;
[0636] V45L+C60V+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[0637] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+V497E;
[0638] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+L478N;
[0639] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T; M28P+V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T;
[0640] V45L+A117S+L149R+S214Q+V258P+A276Q+A364G+S388K+D470T;
[0641] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470V+R483V;
[0642] V45L+A117S+L149R+S214Y+V258P+A276S+A364G+S388K+D470T+R483V;
[0643] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+N395D;
[0644] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+T477K;
[0645] V45L+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K;
[0646] V45L+Q61R+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T;
[0647] V45L+A117S+L149R+S214Q+T215I+V258P+A276S+A364G+S388K+D470T;
[0648] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+Q496E;
[0649] V45L+A117S+L149R+G187K+S214Q+V258P+A276S+A364G+S388K+D470T;
[0650] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+W495I;
[0651] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+V498I;
[0652] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470K+R483V;
[0653] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+V500V; D11E+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K;
[0654] V45L+A117S+L149R+A170S+S214Q+V258P+A276S+A364G+S388K+D470T;
[0655] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+Y391V+D470T;
[0656] V45L+A117S+L149R+S214Q+V258P+A276S+Q314A+A364G+S388K+D470T;
[0657] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+T477V; A25W+V45L+A79C+L149R+S214E+V258P+A276S+A364G;
[0658] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394Q;
[0659] V45L+A117S+L149R+S214Q+H219V+V258P+A276S+A364G+S388K+D470T;
[0660] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+Q496Q;
[0661] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+C375A+S388K+G394A+D470T+R483V;
[0662] V45L+A117S+L149R+D192E+S214Q+V258P+A276S+H358D+A364G;
[0663] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+A472L;
[0664] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+A499Y;
[0665] V45L+A117S+L149R+S214Q+T215V+V258P+A276S+A364G+S388K+D470T;
[0666] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+Q385C+S388K+D470T;
[0667] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388A+D470T;
[0668] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388H+D470T;
[0669] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+T480N;
[0670] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+V497P;
[0671] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+A499L;
[0672] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+S501N;
[0673] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+D470T;
[0674] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+Q384A+S388K;
[0675] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+C375S+S388K+G394A+D470T+R483V;
[0676] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388L+D470T+R483V;
[0677] V45L+A79C+S92D+L149R+V258P+A276S+A364G+S388K;
[0678] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V+C540A;
[0679] V45N+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T;
[0680] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394A;
[0681] V45L+C69S+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[0682] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+V498I;
[0683] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G;
[0684] V45L+A117S+L149R+S214Q+H219I+V258P+A276S+A364G+S388K+D470T;
[0685] V45L+A117S+L149R+N163H+S214Q+V258P+A276S+A364G+S388K+D470T;
[0686] V45L+L149R+S214Q+V258P+A276S+H358D+A364G;
[0687] V45L+A117S+L149R+S214Q+V258P+A276S+Q314A+H358D+A364G+S388K;
[0688] V45L+A117S+L149R+S173Y+S214Q+V258P+A276S+H358D+A364G+S388K;
[0689] V45L+A117S+L149R+S214E+V258P+A276S+H358D+A364G+S388K;
[0690] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394D; A25W+V45L+A79C+L149R+V258P+A276S+A364G;
[0691] V45L+L149R+S214Q+V258P+A276S+A286E+A364G+S388K;
[0692] V45L+Q61R+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K;
[0693] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+T366V+S388K;
[0694] V45L+A117S+L149R+D192E+S214Q+V258P+A276S+H358D+A364G;
[0695] V45L+A117S+L149R+T180Q+S214Q+V258P+A276S+H358D+A364G+S388K;
[0696] V45L+A117S+L149R+S214Q+T215I+V258P+A276S+H358D+A364G+S388K;
[0697] V45L+A117S+L149R+S214Q+W250Y+V258P+A276S+H358D+A364G+S388K;
[0698] V45L+L149R+S214Q+T215I+V258P+A276S+A364G+S388K;
[0699] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+N476D;
[0700] V45L+D113T+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V;
[0701] V45L+A117S+L149R+S214Q+T215K+V258P+A276S+A364G+S388K+D470T+R483V;
[0702] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K;
[0703] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+T477V;
[0704] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+L478P;
[0705] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S481A; A25W+V45L+L149R+S214Q+V258P+A276S+A364G+S388K;
[0706] V45L+A117S+L149R+T211H+S214Q+V258P+A276S+A364G+S388K+D470T;
[0707] V45L+A117S+L149R+S214Q+T215K+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[0708] V45L+A79C+L149R+V258P+A276S+L281V+A364G;
[0709] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+R483V;
[0710] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+V500T;
[0711] V45L+A117S+L149R+S214Q+V258P+A276S+V350L+H358D+A364G+S388K;
[0712] V45L+A117S+L149R+G187K+S214Q+V258P+A276S+H358D+A364G+S388K;
[0713] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+C375L+S388K+G394A+D470T+R483V;
[0714] V45L+L149R+A170S+S214Q+V258P+A276S+A364G+S388K;
[0715] V45L+A117S+L149R+S214E+V258P+A276S+A364G+S388K+D470T;
[0716] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470V+R483V;
[0717] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+V500V;
[0718] V45L+Q61K+L149R+S214Q+V258P+A276S+A364G+S388K;
[0719] V45L+L149R+N168G+S214Q+V258P+A276S+A364G+S388K;
[0720] V45L+A117S+L149R+N163H+S214Q+V258P+A276S+H358D+A364G+S388K;
[0721] V45L+A79C+D95D+L149R+V258P+A276S+A364G+S388K;
[0722] V45L+Q77E+A79C+L149R+V258P+A276S+A364G+S388K;
[0723] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+V497W;
[0724] V45L+L149R+S214Q+V258P+A276S+S282N+A364G+S388K;
[0725] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388R;
[0726] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S481S;
[0727] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+V500T;
[0728] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V+C540L;
[0729] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V+C522S;
[0730] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+W495S;
[0731] V45L+L149R+S214Q+V258P+A276S+Q314A+A364G+S388K;
[0732] V45L+D113T+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K;
[0733] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+V497W;
[0734] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V+C540S;
[0735] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+C396S+D470T+R483V;
[0736] V45L+T70R+L149R+S214Q+V258P+A276S+A364G+S388K;
[0737] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+N474G;
[0738] V45L+A117S+L149R+S214Q+V258P+A276S+S282N+H358D+A364G+S388K;
[0739] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+Q496Q;
[0740] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+S389V+D470T;
[0741] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+C396A+D470T+R483V;
[0742] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S501E; A25W+V45L+L149R+S214E+V258P+A276S+A364G;
[0743] V45L+L149R+S214Q+W250Y+V258P+A276S+A364G+S388K;
[0744] V45L+L149R+G187K+S214Q+V258P+A276S+A364G+S388K;
[0745] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+N476N;
[0746] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S473K;
[0747] V45L+A117S+L149R+G187L+S214Q+V258P+A276S+H358D+A364G+S388K; C40L+V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[0748] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+Q496E; A25W+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K;
[0749] V45L+L149R+V258P+A276S+L281V+H358T+A364G+S388K;
[0750] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388A;
[0751] V45L+A117S+L149R+N168G+S214Q+V258P+A276S+H358D+A364G+S388K;
[0752] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S389H; M28P+V45L+L149R+S214Q+V258P+A276S+A364G+S388K;
[0753] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+T480L;
[0754] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+Q384A+S388K;
[0755] V45L+A93S+L149R+A252S+H334D; C40A+V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[0756] V45L+L149R+G187L+S214Q+V258P+A276S+A364G+S388K;
[0757] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+Q385C+S388K;
[0758] V45L+L149R+S214Q+V258P+A276S+A286S+A364G+S388K;
[0759] V45L+S92D+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K;
[0760] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388L;
[0761] V45L+A117S+L149R+S214Q+V258P+A276S+A286E+A364G+S388K; D9E+V45L+L149R+S214Q+V258P+A276S+A364G+S388K;
[0762] V45L+L149R+S173Y+S214Q+V258P+A276S+A364G+S388K;
[0763] V45L+A117S+L149R+A170S+S214Q+V258P+A276S+H358D+A364G+S388K;
[0764] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+Y391V;
[0765] V45L+A117S+L149R+S214Q+V258P+A276S+L281V+A364G+S388K;
[0766] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+G394D;
[0767] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+S473G;
[0768] V45L+A79C+L149R+V258P+A276S+H358T+A364G+S388K;
[0769] V45L+L149R+S214Q+V258P+A276Q+A364G+S388K; A25W+V45L+L149R+S214E+V258P+A276S+H358T+A364G;
[0770] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+T480N; D9E+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K;
[0771] V45L+A117S+L149R+S214Q+H219I+V258P+A276S+H358D+A364G+S388K; C40S+V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V; C40V+V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V; A25W+V45L+L149R+S214E+V258P+A276S+A286E+A364G;
[0772] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+G394A;
[0773] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+A499L; A25W+V45L+Q61K+L149R+S214E+V258P+A276S+A364G;
[0774] V45L+A117S+L149R+S214Q+T215V+V258P+A276S+H358D+A364G+S388K; A25W+V45L+L149R+V258P+A276S+H358T+A364G+S388K;
[0775] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+W495E; A25W+V45L+A79C+L149R+V258P+A276S;
[0776] V45L+L149R+S214Q+V258P+A276S+V350L+A364G+S388K; D11E+V45L+L149R+S214Q+V258P+A276S+A364G+S388K;
[0777] V45L+L149R+H219I+V258P+A276S+H358T+A364G+S388K;
[0778] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+C396V+D470T+R483V;
[0779] V45N+L149R+S214Q+V258P+A276S+A364G+S388K;
[0780] V45L+A117S+L149R+S214Q+H219V+V258P+A276S+H358D+A364G+S388K;
[0781] V45N+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K;
[0782] V45L+S92D+L149R+S214Q+V258P+A276S+A364G+S388K;
[0783] V45L+L149R+V258P+A276S+H358T+A364G;
[0784] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+L478P;
[0785] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+S481A;
[0786] V45L+A117S+L149R+S214Q+V258P+A276S+Q314A+A364G+S388K; A25W+V45L+L149R+T211H+S214E+V258P+A276S+A364G; A25W+V45L+L149R+S214E+H219V+V258P+A276S+A364G;
[0787] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S389V;
[0788] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+V393H;
[0789] V45L+A117S+L149R+S214Q+V258P+A276Q+H358D+A364G+S388K;
[0790] V45L+A117S+N127D+L149R+S214Q+V258P+A276S+H358D+A364G+S388K;
[0791] V45L+L149R+W250Y+V258P+A276S+H358T+A364G+S388K; D9E+V45L+L149R+V258P+A276S+H358T+A364G+S388K;
[0792] V45L+L149R+H219V+V258P+A276S+H358T+A364G+S388K;
[0793] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+A472L; A25W+V45L+L149R+V258P+A276S+A364G;
[0794] V45L+A117S+L149R+G187K+S214Q+V258P+A276S+A364G+S388K;
[0795] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+L478N;
[0796] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+V393R;
[0797] V45L+A117S+L149R+S214E+V258P+A276S+A364G+S388K;
[0798] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+T366V+S388K;
[0799] V45L+A117S+L149R+S214Q+V258P+A276S+H358T+A364G+S388K; D11E+A25W+V45L+L149R+S214E+V258P+A276S+A364G;
[0800] V45L+T70R+A117S+L149R+C161V+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[0801] V45L+A117S+L149R+T211H+S214Q+V258P+A276S+H358D+A364G+S388K;
[0802] V45L+L149R+V258P+A276S+Q314A+H358T+A364G+S388K; D11E+V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K;
[0803] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+G394Q;
[0804] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+N395D;
[0805] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+V393H;
[0806] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+S501E;
[0807] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+S528H;
[0808] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[0809] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388L;
[0810] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+C396L+D470T+R483V;
[0811] V45L+L149R+T180Q+S214Q+V258P+A276S+A364G+S388K;
[0812] V45L+D113T+L149R+S214Q+V258P+A276S+A364G+S388K;
[0813] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+T480L;
[0814] V45L+A93S+L149R+A252S+H334D;
[0815] V45L+A93S+L149R+V234P+A252S;
[0816] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388H; A25W+V45L+Q61R+L149R+S214E+V258P+A276S+A364G;
[0817] V45L+A117S+L149R+S214Q+T215K+V258P+A276S+H358D+A364G+S388K+D470T;
[0818] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+S389H;
[0819] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+T366I+S388K;
[0820] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+N474G; A25W+V45L+L149R+S214E+V258P+A276S+L281V+A364G; D9E+A25W+V45L+L149R+S214E+V258P+A276S+A364G;
[0821] V45L+A117S+L149R+S214Q+T215K+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[0822] V45L+A117S+L149R+S214Y+V258P+A276S+H358D+A364G+S388K;
[0823] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+V393R;
[0824] V45L+Q61R+L149R+V258P+A276S+H358T+A364G+S388K;
[0825] V45L+L149R+S214Q+V258P+A276S+A364G+S388K;
[0826] V45L+D113T+L149R+V258P+A276S+H358T+A364G+S388K;
[0827] V45L+A117S+L149R+S214Q+V258P+A276S+A286S+A364G+S388K;
[0828] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388R;
[0829] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+A499Y;
[0830] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+V500V;
[0831] V45L+Q61R+L149R+S214Q+V258P+A276S+A364G+S388K;
[0832] V45L+L149R+S214E+V258P+A276S+H358T+A364G;
[0833] V45L+A117S+L149R+S214Q+V258P+A276Q+A364G+S388K;
[0834] V45L+L149R+V258P+A276S+L281V+A364G;
[0835] V45L+A117S+L149R+S214Q+W250Y+V258P+A276S+A364G+S388K;
[0836] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+T480N;
[0837] V45L+A117S+L149R+G187S+S214Q+V258P+A276S+A364G+S388K; A25W+V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K;
[0838] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K;
[0839] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+N476N;
[0840] A25W+V45L+L149R+S214E+V258P+A276Q+A364G;
[0841] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+N476D;
[0842] V45L+L149R+S214Q+V258P+A276S+L281V+A364G;
[0843] V45L+A93S+L149R+A252S+H334D+A340G;
[0844] V45L+A93S+L149R+A252S+H334D;
[0845] V45L+A93S+L149R+A252S+H334D;
[0846] V45L+L149R+A252S+H334D;
[0847] V45L+N127D+L149R+V258P+A276S+A364G+S388K;
[0848] V45L+L149R+V258P+A276S+H358T+A364G+S388K;
[0849] V45L+L149R+V258P+A276S+A364G+S388K; D9E+V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K;
[0850] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+S481S;
[0851] V45L+L149R+N168G+V258P+A276S+A364G;
[0852] V45L+L149R+T180Q+V258P+A276S+H358T+A364G+S388K;
[0853] V45L+L149R+G187L+V258P+A276S+A364G+S388K;
[0854] V45L+L149R+W250Y+V258P+A276S+A364G+S388K;
[0855] V45L+L149R+V258P+A276S+A286E+A364G+S388K;
[0856] V45L+L149R+V258P+A276S+S282N+A364G+S388K; A25W+V45L+L149R+V258P+A276S+A364G+S388K;
[0857] V45L+L149R+S214Q+V258P+A276S+H358T+A364G;
[0858] V45L+L149R+S173Y+V258P+A276S+A364G;
[0859] V45L+A117S+L149R+S214Q+H219V+V258P+A276S+A364G+S388K;
[0860] V45L+A93S+L149R+A252S+H334D;
[0861] V45L+A93S+L149R+A252S+H334D+A340G;
[0862] V45L+L149R+S190E+D446T+R459V; A25W+V45L+L149R+V258P+A276S+H358T; A25W+V45L+S92D+L149R+S214E+V258P+A276S+A364G; A25W+V45L+L149R+S214E+V258P+A276S+V350L+A364G; A25W+V45L+L149R+S214Q+V258P+A276S+A364G;
[0863] V45L+L149R+N168G+V258P+A276S+A364G+S388K;
[0864] V45L+A117S+L149R+V258P+A276S+A364G+S388K; A25W+V45L+L149R+V258P+A276S+H358T+A364G;
[0865] V45L+L149R+V258P+N260H+A276S+A364G+S388K;
[0866] V45L+L149R+T215I+V258P+A276S+A364G+S388K; A25W+V45L+L149R+V258P+A276Q+A364G;
[0867] V45L+T70R+A117S+L149R+C161L+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[0868] A25W+V45L+L149R+S214E+V258P+A276S;
[0869] V45L+A117S+L149R+S214Q+V258P+A276S+A286S+H358D+A364G+S388K;
[0870] V45L+L149R+T211H+S214Q+V258P+A276S+A364G+S388K;
[0871] V45L+Q61K+L149R+V258P+A276S+H358T+A364G;
[0872] V45L+L149R+V258P+A276S+Q314A+H358T+A364G;
[0873] V45L+L149R+T180Q+V258P+A276S+A364G+S388K;
[0874] V45L+L149R+V258P+A276S+Q314A+A364G+S388K; A25W+V45L+L149R+V258P+A276S+A286S+A364G;
[0875] V45L+L149R+S190E+D446T;
[0876] V45L+L149R+V258P+A276S+A364G;
[0877] V45L+L149R+A170S+V258P+A276S+A364G;
[0878] V45L+L149R+V258P+A276Q+A364G;
[0879] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V+C522A;
[0880] V45L+L149R+H219I+V258P+A276S+H358T+A364G;
[0881] V45L+L149R+V258P+A276S+V350L+A364G+S388K; D11E+V45L+L149R+V258P+A276S+A364G+S388K;
[0882] V45L+D113T+L149R+V258P+A276S+A364G+S388K;
[0883] V45L+L149R+G187K+V258P+A276S+A364G+S388K; M28P+V45L+L149R+V258P+A276S+A364G+S388K;
[0884] V45L+Q61R+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V; A25W+V45L+L149R+S214Q+V258P+A276S;
[0885] V45L+A117S+L149R+S214Q+T215I+V258P+A276S+A364G+S388K; A25W+V45L+L149R+V258P+A276S+S388K; A25W+V45L+L149R+S214E+H219I+V258P+A276S+A364G;
[0886] V45L+A93S+L149R+V234P+A252S+H334D;
[0887] V45L+L149R+T211H+V258P+A276S+H358T+A364G+S388K; A25W+V45L+A117S+L149R+S214E+V258P+A276S+A364G;
[0888] V45L+L149R+S173Y+V258P+A276S+A364G+S388K; A25W+V45L+L149R+V258P+A276S+Q314A+A364G;
[0889] V45L+L149R+G187L+V258P+A276S+H358T+A364G;
[0890] V45L+L149R+T215V+V258P+A276S+H358T+A364G;
[0891] V45L+T70R+L149R+V258P+A276S+A364G+S388K;
[0892] V45L+N127D+L149R+V258P+A276S+A364G;
[0893] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+Q496R;
[0894] V45L+L149R+W250Y+V258P+A276S+A364G;
[0895] V45L+L149R+V258P+A276S+V350L+H358T+A364G; D9E+V45L+L149R+V258P+A276S+H358T+A364G;
[0896] V45L+L149R+T211H+V258P+A276S+H358T+A364G; A25W+V45L+L149R+W250Y+A276Q+A364G;
[0897] V45L+L149R+V258P+A276S+L281V+A364G+S388K;
[0898] V45L+L149R+V258P+A276S+S282N+H358T+A364G;
[0899] V45L+L149R+T215I+V258P+A276S+H358T+A364G; A25W+V45L+L149R+S173Y+V258P+A276S+A364G;
[0900] V45L+Q61K+L149R+V258P+A276S+A364G+S388K;
[0901] V45L+L149R+T180Q+V258P+A276S+A364G;
[0902] V45L+A117S+L149R+A170S+S214Q+V258P+A276S+A364G+S388K;
[0903] V45L+Q61R+A117S+L149R+S214Q+V258P+A276S+A364G+S388K; A25W+V45L+L149R+S214E+T215V+V258P+A276S+A364G;
[0904] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+V497P;
[0905] V45L+L149R+V258P+A276S+Q314A+A364G;
[0906] V45L+A117S+L149R+V258P+A276S+A364G;
[0907] V45L+A117S+L149R+V258P+A276S+H358T+A364G+S388K;
[0908] V45L+L149R+N168G+V258P+A276S+H358T+A364G+S388K; A25W+V45L+Q61K+L149R+V258P+A276S+A364G;
[0909] V45L+L149R+S214E+V258P+A276S+L281V+A364G;
[0910] V45N+L149R+V258P+A276S+A364G+S388K;
[0911] V45L+L149R+V258P+A276S+A286E+H358T+A364G; D9E+V45L+L149R+V258P+A276S+A364G+S388K;
[0912] V45L+S92D+L149R+V258P+A276S+A364G+S388K;
[0913] V45L+A117S+L149R+T180Q+S214Q+V258P+A276S+A364G+S388K;
[0914] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388H;
[0915] V45L+A117S+L149R+S214Q+T215V+V258P+A276S+A364G+S388K;
[0916] V45L+A117S+L149R+S214Q+V258P+A276S+V350L+A364G+S388K; A25W+V45L+L149R+S214E+T215I+V258P+A276S+A364G;
[0917] V45L+N127D+L149R+V258P+A276S+H358T+A364G+S388K; A25W+V45L+L149R+V258P+A276S+A286E+A364G;
[0918] V45L+L149R+N168G+V258P+A276S+L281V+A364G;
[0919] V45L+Q61R+L149R+V258P+A276S+H358T+A364G;
[0920] V45L+L149R+G187S+V258P+A276S+A364G+S388K;
[0921] V45L+L149R+V258P+A276S+L281V+Q314A+A364G;
[0922] V45L+L149R+V258P+A276S+L281V+H358T+A364G;
[0923] V45L+L149R+A170S+V258P+A276S+H358T+A364G;
[0924] V45L+L149R+A170S+V258P+A276S+A364G+S388K;
[0925] V45L+L149R+T215V+V258P+A276S+A364G+S388K;
[0926] V45L+L149R+V258P+A276Q+L281V+A364G;
[0927] V45L+T70R+A117S+L149R+S214Q+C243S+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[0928] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V+C522V; A25W+V45L+L149R+V258P+A276S+Q314A;
[0929] V45L+L149R+V258P+A276Q+H358T+A364G+S388K; A25W+V45N+L149R+S214E+V258P+A276S+A364G;
[0930] V45L+L149R+V258P+A276S+A286E+A364G;
[0931] V45L+L149R+V258P+A276S+A286S+H358T+A364G; A25W+V45L+L149R+G187S+V258P+A276S+A364G;
[0932] V45L+L149R+T180Q+V258P+A276S+L281V+A364G; A25W+V45L+L149R+A276Q+L281V+A364G;
[0933] V45L+S92D+L149R+V258P+A276S+L281V+A364G;
[0934] V45L+Q61R+L149R+V258P+A276S+L281V+A364G;
[0935] V45L+L149R+A170S+V258P+A276S+L281V+A364G; D11E+A25W+V45L+L149R+V258P+A276S+A364G; A25W+V45L+Q61R+L149R+V258P+A276S+A364G; A25W+V45L+L149R+T215V+V258P+A276S+A364G; D9E+V45L+L149R+V258P+A276S+L281V+A364G; A25W+V45L+L149R+V258P+A276S+V350L+A364G;
[0936] V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+A364G+S388K;
[0937] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+Y391V;
[0938] V45L+A117S+L149R+N168G+S214Q+V258P+A276S+A364G+S388K;
[0939] V45L+D113T+A117S+L149R+S214Q+V258P+A276S+A364G+S388K; A25W+V45L+L149R+V258P+A276S+A286E; A25W+V45L+L149R+V258P+A276S+L281V; A25W+V45L+D113T+L149R+V258P+A276S;
[0940] V45L+L149R+H219V+V258P+A276S+L281V+A364G;
[0941] V45L+L149R+T180Q+V258P+A276S+H358T+A364G;
[0942] V45L+L149R+T215V+V258P+A276S+L281V+A364G; A25W+V45L+L149R+V258P+A276S+S282N+A364G; A25W+V45L+L149R+T215I+V258P+A276S+A364G; A25W+V45L+L149R+H219I+V258P+A276S+A364G;
[0943] V45L+A117S+L149R+V258P+A276S+L281V+A364G;
[0944] D9E+A25W+V45L+L149R+V258P+A276S+A364G;
[0945] V45L+L149R+S214Y+V258P+A276S+A364G+S388K; A25W+V45L+L149R+T180Q+V258P+A276S+A364G; A25W+V45L+L149R+V258P+A276S+L281V+A364G;
[0946] V45L+N127D+L149R+V258P+A276S+L281V+A364G;
[0947] V45L+L149R+S173Y+V258P+A276S+H358T+A364G;
[0948] V45L+Q61R+L149R+V258P+A276S+A364G+S388K; M28P+V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K;
[0949] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388A;
[0950] V45N+A117S+L149R+S214Q+V258P+A276S+A364G+S388K;
[0951] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+T477K; A25W+V45L+L149R+T180Q+V258P+A276S; A25W+V45L+L149R+V258P+A276S+A286S; A25W+V45L+L149R+G187S+S214E+V258P+A276S+A364G;
[0952] V45L+L149R+V258P+A276S+L281V+A286E+A364G; A25W+V45L+L149R+W250Y+V258P+A276S+A364G; A25W+V45L+L149R+V258P+N260H+A276S+A364G;
[0953] V45L+L149R+V258P+A276S+L281V+V350L+A364G; A25W+V45L+L149R+A170S+V258P+A276S+A364G;
[0954] V45L+L149R+V258P+A276S+L281V+A286S+A364G;
[0955] V45L+L149R+V258P+A276S+L281V+S282N+A364G; D11E+V45L+L149R+V258P+A276S+L281V+A364G;
[0956] V45L+Q61K+L149R+V258P+A276S+L281V+A364G;
[0957] V45L+L149R+T215I+V258P+A276S+L281V+A364G; A25W+V45L+S92D+L149R+V258P+A276S+A364G;
[0958] V45L+L149R+S214Y+V258P+A276S+L281V+A364G;
[0959] V45L+L149R+T211H+V258P+A276S+L281V+A364G; A25W+V45L+L149R+G187L+V258P+A276S+A364G;
[0960] V45L+S92D+L149R+V258P+A276S+H358T+A364G;
[0961] V45L+L149R+G187L+A276Q+L281V+A364G;
[0962] V45L+L149R+A276Q+L281V+V350L+A364G;
[0963] V45L+L149R+A276Q+L281V+A364G+S388K;
[0964] V45L+A117S+L149R+S214Y+V258P+A276S+A364G+S388K; A25W+V45L+S92D+L149R+V258P+A276S; A25W+V45L+L149R+G187L+V258P+A276S; A25W+V45L+L149R+W250Y+V258P+A276S;
[0965] V45L+D113T+L149R+V258P+A276S+A364G;
[0966] V45L+L149R+G187K+V258P+A276S+H358T+A364G;
[0967] V45L+L149R+N163H+V258P+A276S+L281V+A364G; A25W+V45L+T70R+L149R+V258P+A276S+A364G;
[0968] V45L+L149R+S173Y+V258P+A276S+L281V+A364G;
[0969] V45L+L149R+G187L+V258P+A276S+L281V+A364G;
[0970] V45L+L149R+G187K+V258P+A276S+L281V+A364G;
[0971] V45L+L149R+W250Y+V258P+A276S+H358T+A364G;
[0972] V45L+L149R+T211H+V258P+A276S+A364G+S388K;
[0973] V45L+L149R+N163H+V258P+A276S+A364G+S388K;
[0974] V45L+T70R+L149R+A276Q+L281V+A364G;
[0975] V45L+S92D+L149R+A276Q+L281V+A364G;
[0976] V45L+D113T+L149R+A276Q+L281V+A364G;
[0977] V45L+L149R+A276Q+L281V+Q314A+A364G;
[0978] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+S389V; A25W+V45L+Q61K+L149R+V258P+A276S; D9E+A25W+V45L+L149R+V258P+A276S;
[0979] V45L+T70R+L149R+V258P+A276S+A364G;
[0980] V45L+L149R+V258P+A276S+A286S+A364G+S388K; A25W+V45L+L149R+S214Y+V258P+A276S+A364G; A25W+V45L+D113T+L149R+V258P+A276S+A364G;
[0981] V45L+T70R+L149R+V258P+A276S+L281V+A364G; A25W+V45L+N127D+L149R+V258P+A276S+A364G;
[0982] V45L+T70R+L149R+V258P+A276S+H358T+A364G;
[0983] V45L+L149R+N163H+V258P+A276S+A364G;
[0984] V45L+L149R+T180Q+A276Q+L281V+A364G;
[0985] V45L+L149R+A276Q+L281V+A286S+A364G; A25W+V45L+L149R+A170S+V258P+A276S; A25W+V45L+T70R+L149R+V258P+A276S; A25W+V45L+L149R+S214E+V258P+A276S+A286S+A364G;
[0986] V45L+L149R+V258P+A276S+A286S+H358T+A364G+S388K;
[0987] V45L+L149R+H219I+V258P+A276S+L281V+A364G; A25W+V45L+A117S+L149R+V258P+A276S+A364G; A25W+V45L+L149R+N168G+V258P+A276S+A364G;
[0988] V45L+L149R+N168G+A276Q+L281V+A364G;
[0989] V45L+L149R+S173Y+A276Q+L281V+A364G;
[0990] V45L+L149R+W250Y+A276Q+L281V+A364G;
[0991] V45L+A117S+L149R+S173Y+S214Q+V258P+A276S+A364G+S388K;
[0992] A25W+V45L+L149R+A276Q+A286E+A364G; A25W+V45L+L149R+A276Q+A364G+S388K;
[0993] V45L+N127D+L149R+V258P+A276S+H358T+A364G; A25W+V45L+L149R+V258P+A276S;
[0994] V45L+N127D+L149R+A276Q+L281V+A364G;
[0995] V45L+L149R+A276Q+L281V+A286E+A364G;
[0996] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+V500T; A25W+V45L+A117S+L149R+V258P+A276S; A25W+V45L+L149R+H219V+V258P+A276S+A364G;
[0997] V45L+L149R+S173Y+V258P+A276S+H358T+A364G+S388K; D11E+V45L+L149R+V258P+A276S+H358T+A364G;
[0998] V45L+A79C+L149R+V258P+A276S+N355G+A364G+S388K; A24K+V45L+L149R+V258P+A276S+A364G;
[0999] V45L+L149R+V258P+A276S+S282N+A364G;
[1000] V45L+A117S+L149R+A276Q+L281V+A364G;
[1001] V45L+L149R+N260H+A276Q+L281V+A364G;
[1002] V45L+A117S+L149R+T211H+S214Q+V258P+A276S+A364G+S388K; A25W+V45L+L149R+N168G+V258P+A276S; A25W+V45L+L149R+G187S+V258P+A276S; A25W+V45L+L149R+V258P+A276S+V350L; A25W+V45L+Q61R+L149R+V258P+A276S; A25W+V45L+L149R+G187L+S214E+V258P+A276S+A364G;
[1003] V45L+L149R+G187S+V258P+A276S+L281V+A364G; A25W+V45L+L149R+N163H+V258P+A276S+A364G; A25W+V45L+L149R+G187K+V258P+A276S+A364G;
[1004] V45N+L149R+V258P+A276S+L281V+A364G;
[1005] V45L+L149R+A276Q+L281V+A364G;
[1006] V45L+L149R+V258P+N260H+A276S+H358T+A364G;
[1007] V45L+L149R+A276Q+S282N+A364G;
[1008] V45L+S92D+A117S+L149R+S214Q+V258P+A276S+A364G+S388K; A25W+V45L+L149R+V258P+A276S+S282N; A25W+V45L+L149R+S173Y+V258P+A276S; A25W+V45L+L149R+A276Q+A286S+A364G;
[1009] V45L+D113T+L149R+V258P+A276S+L281V+A364G;
[1010] V45L+L149R+S214Q+V258P+A276S+L281V+A364G+S388K;
[1011] V45L+D113T+L149R+V258P+A276S+H358T+A364G; A25W+V45L+L149R+T215V+V258P+A276S;
[1012] V45L+L149R+N168G+V258P+A276S+H358T+A364G;
[1013] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+A472L;
[1014] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+S473K; A25W+V45L+L149R+T215I+V258P+A276S; A25W+V45L+L149R+T211H+V258P+A276S; A25W+V45L+L149R+V258P+A276Q;
[1015] V45L+L149R+S214Q+T215V+V258P+A276S+A364G+S388K;
[1016] V45L+L149R+N163H+V258P+A276S+H358T+A364G+S388K;
[1017] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+A499L;
[1018] V45L+L149R+V258P+A276S+V350L+A364G;
[1019] V45L+A79C+A117S+L149R+V258P+A276S+A364G+S388K; A25W+V45L+D113T+L149R+A276Q+A364G; A25W+V45N+L149R+V258P+A276S+A364G;
[1020] V45L+T70R+L149R+A276Q+A364G; A25W+V45L+L149R+H219I+V258P+A276S;
[1021] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+V498I; M28P+V45L+L149R+V258P+A276S+A364G; A25W+V45L+T70R+L149R+A276Q+A364G; A25W+V45L+L149R+A276Q+Q314A+A364G;
[1022] V45L+L149R+A170S+V258P+A276S+H358T+A364G+S388K; A25W+V45L+L149R+S214Y+V258P+A276S;
[1023] V45L+L149R+S214Y+V258P+A276S+H358T+A364G;
[1024] V45L+L149R+A276Q+L281V+H358T+A364G; A25W+V45L+L149R+H219V+V258P+A276S;
[1025] V45L+A117S+L149R+N163H+S214Q+V258P+A276S+A364G+S388K; D11E+A25W+V45L+L149R+V258P+A276S;
[1026] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+N527H; A25W+V45L+A117S+L149R+A276Q+A364G;
[1027] V45L+L149R+V258P+L281V+A364G; A25W+V45L+L149R+G187L+A276Q+A364G;
[1028] V45N+L149R+V258P+A276S+H358T+A364G;
[1029] V45L+A117S+L149R+S214Q+V258P+A276S+N355G+H358D+A364G+S388K+D470T+R483V;
[1030] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388H+D470T+R483V; A25W+V45L+L149R+A276Q+A364G;
[1031] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+V497E;
[1032] A25W+V45L+L149R+N163H+A276Q+A364G;
[1033] A25W+V45L+L149R+S173Y+A276Q+A364G;
[1034] A25W+V45L+L149R+A276Q+S282N+A364G;
[1035] A25W+V45L+L149R+A276Q+H358T+A364G;
[1036] A25W+V45L+L149R+T180Q+A276Q+A364G;
[1037] V45L+A117S+L149R+V258P+A276S+H358T+A364G;
[1038] V45L+L149R+A276Q+Q314A+A364G;
[1039] V45L+L149R+G187K+V258P+A364G;
[1040] V45L+L149R+A276Q+A286E+A364G; A25W+V45L+N127D+L149R+A276Q+A364G; A25W+V45L+L149R+A170S+A276Q+A364G; A25W+V45L+N127D+L149R+V258P+A276S;
[1041] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+T477V;
[1042] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+G503L; A25W+M28P+V45L+L149R+V258P+A276S+A364G;
[1043] V45L+L149R+A276Q+H358T+A364G; A25W+V45L+L149R+N168G+A276Q+A364G; A25W+V45L+L149R+N260H+A276Q+A364G;
[1044] V45L+A117S+L149R+G187L+S214Q+V258P+A276S+A364G+S388K;
[1045] V45L+A117S+L149R+N163H+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[1046] V45L+A117S+L149R+S214Q+T215K+V258P+A276S+A364G+S388K; A25W+V45L+L149R+G187K+V258P+A276S; A25W+M28P+V45L+L149R+V258P+A276S; A25W+V45N+L149R+V258P+A276S;
[1047] V45L+A117S+L149R+S214Q+V258P+A276S+N355G+H358D+A364G+S388K+D470T;
[1048] V45L+N127D+L149R+A276Q+A364G;
[1049] V45L+L149R+W250Y+A276Q+A364G;
[1050] V45L+L149R+W250Y+V258P+A364G;
[1051] V45L+L149R+N163H+A276Q+L281V+A364G;
[1052] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+Q385C+S388K; A25W+V45L+L149R+S214E+T215K+V258P+A276S+A364G; M28P+V45L+L149R+V258P+A276S+L281V+A364G;
[1053] V45L+L149R+A276Q+A364G+S388K;
[1054] A25W+V45L+L149R+V258P+A364G;
[1055] M28P+V45L+L149R+V258P+A276S+H358T+A364G;
[1056] V45L+A117S+L149R+S214Q+V258P+A276S+N355G+H358D+A364G+S388K;
[1057] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V+C540V;
[1058] V45L+L149R+N168G+A276Q+A364G;
[1059] V45L+A117S+L149R+A276Q+A364G;
[1060] V45L+L149R+N163H+V258P+A276S+H358T+A364G;
[1061] V45L+L149R+T215K+V258P+A276S+H358T+A364G; A24K+V45L+L149R+A276Q+A364G;
[1062] V45L+L149R+A276Q+A286S+A364G;
[1063] V45L+L149R+V258P+A364G;
[1064] V45L+L149R+H219I+V258P+A276S+A364G+S388K;
[1065] V45L+L149R+A170S+A276Q+A364G;
[1066] V45L+L149R+T180Q+A276Q+A364G;
[1067] V45L+L149R+A276Q+V350L+A364G;
[1068] V45L+L149R+V258P+S282N+A364G;
[1069] V45L+L149R+A276Q+A364G;
[1070] V45L+L149R+A276S+A364G;
[1071] V45L+L149R+T215K+V258P+A276S+A364G+S388K;
[1072] V45L+A117S+L149R+S214Q+V258P+A276S+N355G+A364G+S388K+D470T;
[1073] V45L+L149R+V258P+A276S; A25W+V45L+L149R+A276S+A364G;
[1074] V45L+L149R+G187S+V258P+A364G;
[1075] V45L+S92D+L149R+V258P+A276S+H358T+A364G+S388K; A25W+L149R+V258P+A276S+A364G;
[1076] V45L+L149R+G187L+A276Q+A364G; A25W+V45L+V258P+A276S+A364G;
[1077] V45L+L149R+N260H+A276Q+A364G;
[1078] V45L+L149R+W250Y+V258R+A364G;
[1079] V45L+L149R+N163H+A276Q+A364G;
[1080] V45L+S92D+L149R+A276Q+A364G;
[1081] V45L+L149R+S173Y+A276Q+A364G;
[1082] V45L+S92D+L149R+V258P+A364G;
[1083] V45L+L149R+W250Y+V258P+A276S+L281V+A364G;
[1084] V45L+L149R+L281V+A364G;
[1085] V45L+D113T+L149R+A276Q+A364G;
[1086] L149R+V258P+A276S+A364G;
[1087] V45L+L149R+G187S+V258R+A364G;
[1088] V45L+V258P+A276S+A364G;
[1089] V45L+L149R+V258R+A364G+S388K; A25W+V45L+L149R+A364G;
[1090] V45L+L149R+G187K+V258R+A364G;
[1091] V45L+L149R+V258P;
[1092] V45L+L149R+V258R+S282N+A364G;
[1093] V45L+L149R;
[1094] V45L+L149R+V258R+L281V+A364G;
[1095] V45L+L149R+A364G;
[1096] V45L+L149R+S214Q+V258P+A276S+N355G+A364G+S388K;
[1097] V45L+S92N+L149R+V258P+A364G;
[1098] V45L+A117S+L149R+S214Q+V258P+A276S+A286E+H358D+A364G+S388K; A25W+V45L+L149R+S214E+V258P+A276S+N355G+A364G;
[1099] V45L+L149R+G187L+V258P+A276S+A364G;
[1100] V45L+L149R+V258R+A364G;
[1101] V45L+L149R+V258P+A364G+S388K; A25W+V45L+L149R+A276Q+V350L+A364G;
[1102] V45L+L149R+H219V+V258P+A276S+A364G+S388K;
[1103] V45L+L149R+G187K+A364G;
[1104] V45L+L149R+G187S+A364G;
[1105] V45L+A117S+L149R+S214Q+V258P+A276S+N355G+A364G+S388K;
[1106] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+Y386G+S388K+D470T+R483V;
[1107] V45L+L149R+W250Y;
[1108] V45L+S92N+L149R+V258R+A364G; A25W+V45L+L149R+V258P+A276S+N355G+A364G;
[1109] V45L+L149R+V258P+A276S+N355G+A364G+S388K;
[1110] V45L+L149R+G187S;
[1111] V45N+L149R;
[1112] V45L+L149R+S282N; L149R+A364G; Y386G;
[1113] V258P+A276Q;
[1114] V258P+A276S;
[1115] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394D+D470T+R483V;
[1116] A25W+L149R;
[1117] V45L+A276S;
[1118] V45L+S92D+L149R;
[1119] A25W+A276S;
[1120] Q385C;
[1121] V45L+L149R+W250Y+A364G;
[1122] V45L+A276Q;
[1123] V45L+V258P;
[1124] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+Y386G+S388K;
[1125] A25W+V258P;
[1126] A25W+A276Q;
[1127] L149R+W250Y;
[1128] V45L+L149R+V258P+A276S+L281V+N355G+A364G;
[1129] V45L+S388K;
[1130] V45L+L149R+V258P+A276S+N355G+H358T+A364G;
[1131] V45L+A364G;
[1132] V45N+V258P;
[1133] A276S;
[1134] V258P+S388K;
[1135] A25W+V45L;
[1136] A276Q+S388K;
[1137] A276C;
[1138] A276Q;
[1139] A276F;
[1140] W250Y+A276Q;
[1141] A79C;
[1142] A276S+S388K;
[1143] A276Q+L281V;
[1144] V45L+L149R+V258P+A276S+N355G+A364G;
[1145] A276N;
[1146] W250Y+A276S;
[1147] A25W+S388K;
[1148] A276S+L281V;
[1149] G187S+A276Q;
[1150] A25W+V45L+L149R+V258P+A276S+N355G;
[1151] V45L;
[1152] S92D+A276S;
[1153] S19T;
[1154] L149R+V258R;
[1155] V45N+S388K;
[1156] A25W+V45L+S92D+L149R+A276Q+A364G;
[1157] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+S501E H358D;
[1158] A25W+A364G;
[1159] V258P+L281V;
[1160] L149R;
[1161] V45L+L149R+H219V+V258P+A276S+H358T+A364G;
[1162] A25W;
[1163] V258R+A276S;
[1164] V45N;
[1165] G187S+A276S;
[1166] G187K+A276S;
[1167] I469T;
[1168] V45L+S92D;
[1169] V45L+L281V;
[1170] V45N+W250Y;
[1171] V258R+A276Q;
[1172] V45L+V258R;
[1173] W250Y+S388K;
[1174] A25W+V45L+L149R+A276Q+N355G+A364G;
[1175] V45N+G187K;
[1176] A25W+V45L+L149R+S214E+V258P+A276S+Q314A+A364G;
[1177] S388A;
[1178] A276T;
[1179] A25W+V258R;
[1180] G187K+S388K;
[1181] A25W+S92D;
[1182] L281V+S388K;
[1183] V45N+V258R;
[1184] S388H;
[1185] S92D;
[1186] D525L;
[1187] S214Q;
[1188] L281V+A364G;
[1189] A364G;
[1190] S388L;
[1191] S388R;
[1192] S473G;
[1193] S92D+A364G;
[1194] A25W+G187S;
[1195] A25W+G187K;
[1196] W250Y+V258P;
[1197] S92D+V258P;
[1198] S389V;
[1199] A20H;
[1200] W495E;
[1201] G187K+W250Y;
[1202] Y386Y;
[1203] V393H;
[1204] G187L;
[1205] Q61K;
[1206] V45N+S92D;
[1207] G187S+A364G;
[1208] G187S+L281V;
[1209] G187S;
[1210] A286E;
[1211] A276Y;
[1212] V258P;
[1213] Q496E;
[1214] G394A;
[1215] V393R;
[1216] G187S+S388K;
[1217] T366V;
[1218] S389S;
[1219] S92N;
[1220] N527H;
[1221] Q384A;
[1222] V497D;
[1223] A18V;
[1224] Q496Q;
[1225] Q496R;
[1226] S214E;
[1227] P362P;
[1228] S389H;
[1229] V258R;
[1230] A276D;
[1231] L281V;
[1232] V45I;
[1233] A117C;
[1234] N395N;
[1235] Y391Y;
[1236] A24H;
[1237] A472I;
[1238] D470K;
[1239] S473K;
[1240] S473S;
[1241] W495I;
[1242] V497E;
[1243] A24K;
[1244] V45T;
[1245] L471R;
[1246] A472L;
[1247] A20P;
[1248] N395D;
[1249] G394D;
[1250] G394Q;
[1251] G187S+V258R;
[1252] S92D+G187S;
[1253] V45C;
[1254] N476N;
[1255] G207G;
[1256] A364A;
[1257] D470A;
[1258] N474G;
[1259] D470V; and wherein the variant has xylanse activity and wherein the variant has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%, but less than 100% sequence identity to SEQ ID NO: 1, and wherein the variants have increased thermostability measured as increased melting temperature measured by TSA of at least 0.5° C. compared to the xylanase of SEQ ID NO: 1.
[1260] In one aspect, the present invention relates to xylanase variants comprises at least one of the following substitutions or combinations of substitutions:
[1261] V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+A286E+H358D+A364G+Q384A+S388K+V393H+D470T+R483V;
[1262] V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q384A+S388K+G394Q+D470T+R483V;
[1263] V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q384A+S388K+G394A+D470T+R483V;
[1264] V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q384A+S388K+V393H+D470T+R483V;
[1265] V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q384A+S388K+V393H+D470T+R483V;
[1266] V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q384A+S388K+G394A+D470T+R483V;
[1267] V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q384A+S388K+V393H+D470T+R483V;
[1268] V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q384A+S388K+G394A+D470T+R483V;
[1269] V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+A286E+H358D+A364G+Q384A+S388K+V393H+D470T+R483V;
[1270] V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q384A+S388K+V393H+D470T+R483V;
[1271] V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q384A+S388K+G394A+D470T+R483V;
[1272] V45L+A79C+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[1273] V45L+A79C+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[1274] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[1275] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[1276] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[1277] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[1278] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[1279] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[1280] V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V+L530R;
[1281] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[1282] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[1283] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[1284] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[1285] V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+L530R;
[1286] V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V+L530R;
[1287] V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V+L530R;
[1288] V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+D470T+R483V+L530R;
[1289] V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V+L530R;
[1290] V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+D470T+R483V+L530R;
[1291] V45L+A117S+L149R+G187K+S214Q+V258P+A276S+A286E+H358D+A364G+Q384A+S388K+V393H+D470T+R483V;
[1292] V45L+A117S+L149R+G187K+S214Q+V258P+A276S+A286E+H358D+A364G+Q384A+S388K+N395D+D470T+R483V;
[1293] V45L+A117S+L149R+G187K+S214E+T215I+V258P+A276S+A286E+H358D+A364G+S388K+V393H+D470T+R483V;
[1294] V45L+A117S+L149R+G187K+S214E+T215I+V258P+A276S+A286E+H358D+A364G+S388K+N395D+D470T+R483V;
[1295] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+Q385C+S388K+D470T+R483V;
[1296] V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[1297] V45L+A79C+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V;
[1298] V45L+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+D470T+R483V;
[1299] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+T366I+S388K+D470T+R483V;
[1300] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[1301] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+Q384A+S388K+D470T+L530R;
[1302] V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[1303] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[1304] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+V393H+D470T+R483V;
[1305] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394A+D470T+R483V;
[1306] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+V393H+D470T+L530R;
[1307] V45L+A117S+L149R+S214Q+V258P+A276S+A286E+H358D+A364G+S388K+D470T+R483V;
[1308] D11E+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[1309] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+C468V+D470T+R483V;
[1310] V45L+A79C+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[1311] V45L+A79C+L149R+S214E+V258P+A276S+A364G+S388K;
[1312] V45L+A117S+L149R+G187L+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[1313] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+Q384A+S388K+D470T+R483V;
[1314] V45L+A117S+L149R+G187K+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[1315] V45L+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+D470T+L530R;
[1316] V45L+A117S+L149R+S214E+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[1317] V45L+A117S+L149R+G187L+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[1318] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394Q+D470T+R483V;
[1319] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394A+D470T+L530R;
[1320] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+T366V+S388K+D470T+L530R;
[1321] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394Q+D470T+L530R;
[1322] V45L+A117S+L149R+S214Q+V258P+A276S+S282N+H358D+A364G+S388K+D470T+R483V;
[1323] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+N395D+D470T+R483V;
[1324] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N476D+R483V;
[1325] V45L+A117S+L149R+S214Q+V258P+A276S+V350L+H358D+A364G+S388K+D470T+R483V;
[1326] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T477K+R483V;
[1327] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+Q496R;
[1328] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+C468A+D470T+R483V;
[1329] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+W495E;
[1330] V45L+A117S+L149R+S214Q+V258P+A276S+A286E+H358D+A364G+S388K+D470T+L530R;
[1331] V45L+A117S+L149R+G187K+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[1332] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+Y391V+D470T+R483V;
[1333] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[1334] D9E+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[1335] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T477V+R483V;
[1336] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N476N+R483V;
[1337] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+V393R+D470T+R483V;
[1338] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T480L+L530R;
[1339] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S481A+L530R;
[1340] V45L+A117S+L149R+S214Q+W250Y+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[1341] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S481S+R483V;
[1342] V45L+A117S+L149R+S173Y+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[1343] V45L+T70R+A117S+L149R+S214Q+C243V+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[1344] V45L+A117S+L149R+T180Q+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[1345] D11E+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[1346] V45L+A117S+L149R+S214E+V258P+A276S+H358D+A364G+S388K+D470T+L530R N476D+L530R;
[1347] V45L+A117S+L149R+S214Q+V258P+A276S+A286S+H358D+A364G+S388K+D470T+R483V;
[1348] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+Q496Q;
[1349] V45L+A117S+L149R+S214Q+V258P+A276Q+H358D+A364G+S388K+D470T+R483V;
[1350] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+Q496E;
[1351] V45L+Q61R+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[1352] V45L+A117S+L149R+S214Q+V258P+A276S+Q314A+H358D+A364G+S388K+D470T+L530R;
[1353] V45L+A117S+L149R+S214Q+V258P+A276Q+H358D+A364G+S388K+D470T+L530R;
[1354] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L478P+R483V;
[1355] A25W+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[1356] V45L+A117S+L149R+T180Q+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[1357] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+L484K;
[1358] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N474G+L530R;
[1359] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+N395D+D470T+L530R;
[1360] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+T366V+S388K+D470T+R483V;
[1361] V45L+A117S+L149R+N168G+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[1362] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+L484S;
[1363] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[1364] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+L484D;
[1365] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+S528H;
[1366] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+S501N;
[1367] V45L+A117S+L149R+S173Y+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[1368] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+A499L;
[1369] V45L+S92D+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[1370] V45L+A117S+L149R+S214Q+V258P+A276S+Q314A+H358D+A364G+S388K+D470T+R483V;
[1371] V45L+A79C+L149R+S214Q+V258P+A276S+A364G+S388K;
[1372] V45L+A117S+L149R+S214Q+V258P+A276S+N355G+H358D+A364G+S388K+D470T+L530R;
[1373] V45L+A117S+L149R+S214Q+V258P+A276S+V350L+H358D+A364G+S388K+D470T+L530R;
[1374] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S481S+L530R;
[1375] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+Q496E+L530R;
[1376] V45L+A117S+L149R+N168G+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[1377] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+V498I+L530R;
[1378] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470A+R483V;
[1379] V45N+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[1380] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+A499Y;
[1381] V45L+A79C+L149R+V258P+A276S+Q314A+A364G+S388K;
[1382] V45L+A79C+L149R+V258P+A276S+L281V+A364G+S388K;
[1383] V45L+A117S+L149R+S214Q+V258P+A276S+A286S+H358D+A364G+S388K+D470T+L530R;
[1384] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S501N+L530R;
[1385] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N476N+L530R;
[1386] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T477V+L530R;
[1387] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388H+D470T+L530R;
[1388] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L478N+L530R;
[1389] V45L+S92D+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[1390] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+V500V+L530R;
[1391] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+V500V;
[1392] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L478P+L530R;
[1393] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+S501E;
[1394] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+D525L+L530R;
[1395] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+G526T+L530R;
[1396] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N527H+L530R;
[1397] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T477K+L530R;
[1398] M28P+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[1399] D9E+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[1400] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S501E+L530R;
[1401] V45L+A117S+L149R+S214Q+W250Y+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[1402] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+A499L+L530R;
[1403] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+A472I+L530R;
[1404] V45L+A117S+N127D+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[1405] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+V500T+L530R;
[1406] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+N527H;
[1407] V45N+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[1408] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T480N+L530R;
[1409] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+V497P;
[1410] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+V498I;
[1411] V45L+A79C+L149R+S173Y+V258P+A276S+A364G+S388K;
[1412] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T480N+R483V;
[1413] V45L+A117S+L149R+S214Q+H219V+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[1414] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388A+D470T+L530R;
[1415] M28P+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[1416] V45L+A117S+L149R+A170S+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[1417] V45L+A79C+L149R+G187K+V258P+A276S+A364G+S388K;
[1418] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S389H+D470T+L530R;
[1419] V45L+D113T+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[1420] V45L+A117S+L149R+N163H+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[1421] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388A+D470T+R483V;
[1422] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388L+D470T+R483V;
[1423] V45L+Q61R+A79C+L149R+V258P+A276S+A364G+S388K;
[1424] V45L+A79C+L149R+N168G+V258P+A276S+A364G+S388K;
[1425] V45L+A117S+L149R+T211H+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[1426] V45L+A79C+L149R+T215V+V258P+A276S+A364G+S388K;
[1427] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+V500T;
[1428] V45L+A79C+L149R+V258P+A276S+A286S+A364G+S388K;
[1429] V45L+A79C+L149R+H219V+V258P+A276S+A364G+S388K;
[1430] V45L+A79C+L149R+A170S+V258P+A276S+A364G+S388K;
[1431] V45L+D113T+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[1432] V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[1433] V45L+D95N+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394A+D470T;
[1434] V45L+A79C+L149R+V258P+A276S+A364G+S388K;
[1435] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+G394A+D470T+R483V;
[1436] V45L+A93T+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+A499Y;
[1437] V45L+A117S+L149R+S214Q+T215I+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[1438] V45L+A117S+L149R+S214Q+H219I+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[1439] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L478N;
[1440] V45L+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+D470T;
[1441] V45L+A117S+L149R+S214E+V258P+A276S+H358D+A364G+S388K+D470T;
[1442] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+C468L+D470T+R483V;
[1443] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+Q385C+S388K+D470T+L530R;
[1444] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+T366I+S388K+D470T;
[1445] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S473G;
[1446] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L478P;
[1447] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394D+D470T;
[1448] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+Q384A+S388K+D470T+R483V;
[1449] D11E+V45L+A79C+L149R+V258P+A276S+A364G+S388K;
[1450] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+L530R;
[1451] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N529T;
[1452] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394Q+D470T;
[1453] V45L+A117S+L149R+G187L+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[1454] V45L+A79C+L149R+V258P+A276S+A286E+A364G+S388K;
[1455] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+G503L;
[1456] V45L+A117S+L149R+S214Q+V258P+A276S+Q314A+H358D+A364G+S388K+D470T;
[1457] V45L+A117S+L149R+S214Q+V258P+A276S+V350L+H358D+A364G+S388K+D470T;
[1458] V45L+A117S+L149R+G187K+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[1459] V45L+A117S+L149R+S214Q+W250Y+V258P+A276S+H358D+A364G+S388K+D470T;
[1460] V45L+A117S+L149R+S214Q+V258P+A276S+A286E+H358D+A364G+S388K+D470T;
[1461] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+Q384A+S388K+D470T;
[1462] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388R+D470T;
[1463] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S528H;
[1464] V45L+A117S+L149R+S214Q+T215V+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[1465] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+Q496R;
[1466] V45L+A117S+L149R+N163H+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[1467] V45L+A117S+L149R+S214Q+V258P+A276S+S282N+H358D+A364G+S388K+D470T;
[1468] V45L+A117S+L149R+S214Q+V258P+A276Q+H358D+A364G+S388K+D470T;
[1469] D11E+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[1470] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+T366V+S388K+D470T;
[1471] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S473K;
[1472] V45L+A79C+L149R+T180Q+V258P+A276S+A364G+S388K;
[1473] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S481A+R483V;
[1474] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388R+D470T+R483V;
[1475] V45L+A117S+L149R+S214Q+V258P+A276S+Q314A+A364G+S388K+D470T+R483V;
[1476] V45L+S92D+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[1477] V45L+A117S+L149R+S214Q+V258P+N260H+A276S+H358D+A364G+S388K+D470T;
[1478] V45L+A117S+L149R+G187S+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[1479] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T477K;
[1480] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N474G;
[1481] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+N395D+S501N V45L+A117S+N127D+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[1482] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+V393R+D470T;
[1483] V45L+A117S+L149R+S173Y+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[1484] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388H+D470T;
[1485] V45L+A117S+L149R+S214Q+T215V+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[1486] V45L+A117S+L149R+G187S+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[1487] V45L+A117S+L149R+T211H+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[1488] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T480N;
[1489] V45L+A117S+L149R+N168G+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[1490] V45L+A79C+L149R+H219I+V258P+A276S+A364G+S388K;
[1491] V45L+L149R+S214E+V258P+A276S+H358D+A364G+D470T;
[1492] V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V;
[1493] V45L+D113T+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[1494] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+T366V+S388K+D470T+R483V;
[1495] V45L+A117S+L149R+S214Q+V258P+A276S+H358T+A364G+S388K+D470T+R483V;
[1496] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+V393R+D470T+R483V;
[1497] V45N+A79C+L149R+V258P+A276S+A364G+S388K;
[1498] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+Q496Q;
[1499] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+G394Q+D470T+R483V;
[1500] V45L+A79C+L149R+V258P+A276S+V350L+A364G+S388K;
[1501] V45L+L149R+S214E+V258P+A276S+H358D+A364G+D470T;
[1502] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+T366I+S388K+D470T+R483V;
[1503] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+G526T;
[1504] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L484S;
[1505] V45L+A79C+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K;
[1506] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+A499L;
[1507] V45L+A117S+L149R+S214Q+V258P+A276S+H358T+A364G+S388K+D470T+L530R;
[1508] V45L+A79C+D113T+L149R+V258P+A276S+A364G+S388K;
[1509] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+D525L;
[1510] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+V498I;
[1511] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388L+D470T;
[1512] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V;
[1513] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S528H+L530R;
[1514] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+N476D+R483V;
[1515] D9E+V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V;
[1516] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S501E;
[1517] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S481A;
[1518] V45L+A117S+L149R+S214Q+H219V+V258P+A276S+H358D+A364G+S388K+D470T;
[1519] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S481S;
[1520] V45L+A117S+L149R+G187K+S214Q+V258P+A276S+A364G+S388K+D470T+V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+N395D+D470T+R483V;
[1521] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+I469T+D470T+R483V;
[1522] V45L+A79C+N127D+L149R+V258P+A276S+A364G+S388K;
[1523] D9E+V45L+A79C+L149R+V258P+A276S+A364G+S388K;
[1524] V45L+L149R+S214E+V258P+A276S+H358D+A364G+D470T;
[1525] V45L+A117S+L149R+G187L+S214Q+V258P+A276S+A364G+S388K+D470T+R483V;
[1526] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N529T+L530R;
[1527] V45L+A79C+L149R+W250Y+V258P+A276S+A364G+S388K;
[1528] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+V497P;
[1529] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N527H;
[1530] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+Q496Q;
[1531] V45L+A117S+L149R+N168G+S214Q+V258P+A276S+A364G+S388K+D470T+R483V;
[1532] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+N476N+R483V;
[1533] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+T477V+R483V;
[1534] V45L+A117S+L149R+S214Q+V258P+A276S+V350L+A364G+S388K+D470T+R483V;
[1535] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+L478N+R483V;
[1536] V45L+A117S+L149R+S214E+V258P+A276S+A364G+S388K+D470T+R483V;
[1537] M28P+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[1538] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+V393H+D470T+R483V;
[1539] V45L+Q61R+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V;
[1540] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+V497P;
[1541] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+V498I;
[1542] V45L+A117S+L149R+S214Q+V258P+A276S+S282N+H358D+A364G+S388K+D470T+L530R;
[1543] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+C375V+S388K+G394A+D470T+R483V;
[1544] V45L+A117S+L149R+S214Q+V258P+A276S+A286E+A364G+S388K+D470T+R483V;
[1545] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388R+D470T+R483V;
[1546] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470A+R483V;
[1547] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+T477K+R483V;
[1548] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+Q496E;
[1549] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+Q496R;
[1550] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+A499L;
[1551] V45L+L149R+S214E+V258P+A276S+H358D+A364G+D470T;
[1552] V45L+L149R+S214E+V258P+A276S+H358D+A364G+D470T;
[1553] V45L+A117S+L149R+S214Q+T215I+V258P+A276S+H358D+A364G+S388K+D470T;
[1554] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+C468S+D470T+R483V;
[1555] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+Y391V+D470T+R483V;
[1556] V45L+A117S+L149R+S214Q+V258P+A276Q+A364G+S388K+D470T+R483V;
[1557] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+G503L+L530R;
[1558] V45L+A117S+L149R+S214Q+H219I+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[1559] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N476D;
[1560] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+V393H+D470T;
[1561] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V;
[1562] V45L+A117S+L149R+S214Q+V258P+A276S+A286S+A364G+S388K+D470T+R483V;
[1563] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+S501E;
[1564] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+N529T;
[1565] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+S501N, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[1566] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+S481S+R483V;
[1567] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+L478P+R483V;
[1568] D11E+V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V;
[1569] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T477V;
[1570] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+V497P+L530R;
[1571] V45L+A117S+L149R+T211H+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[1572] V45L+A117S+L149R+S214Y+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[1573] V45L+A117S+L149R+S214Q+W250Y+V258P+A276S+A364G+S388K+D470T+R483V;
[1574] V45L+S92D+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V;
[1575] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+N527H;
[1576] V45N+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V;
[1577] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+Q385C+S388K+D470T;
[1578] V45L+A117S+L149R+S173Y+S214Q+V258P+A276S+A364G+S388K+D470T+R483V;
[1579] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388H+D470T+R483V;
[1580] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+S389H+D470T+V45L+A117S+L149R+S214Q+H219V+V258P+A276S+A364G+S388K+D470T+R483V;
[1581] V45L+A79C+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T;
[1582] V45L+A117S+L149R+S214Q+T215I+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[1583] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+Q496E;
[1584] V45L+A117S+L149R+A170S+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[1585] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S389V+D470T+R483V;
[1586] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S389V+D470T+L530R;
[1587] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388A+D470T;
[1588] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S389V+D470T;
[1589] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[1590] V45L+A117S+L149R+S214Q+H219I+V258P+A276S+A364G+S388K+D470T+R483V;
[1591] V45L+A79C+L149R+N163H+V258P+A276S+A364G+S388K;
[1592] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+A499Y;
[1593] V45L+A117S+L149R+S214Q+V258P+A276S+L281V+A364G+S388K+D470T+R483V;
[1594] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+V500T;
[1595] V45L+A117S+L149R+T180Q+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[1596] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+V500V;
[1597] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+G526T;
[1598] V45L+C60L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[1599] V45L+C69L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[1600] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388A+D470T+R483V;
[1601] V45L+A117S+L149R+S214Q+V258P+A276S+A286S+H358D+A364G+S388K+D470T;
[1602] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+V497D;
[1603] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470A+L530R;
[1604] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+D525L;
[1605] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N476N;
[1606] V45L+A117S+L149R+S214Q+V258P+A276S+L281V+A364G+S388K+D470T;
[1607] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+Q384A+S388K+D470T;
[1608] V45L+A117S+L149R+S214Q+V258P+A276S+A286E+A364G+S388K+D470T;
[1609] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+T477K;
[1610] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S389H+D470T;
[1611] V45L+A117S+L149R+S214Y+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[1612] V45L+A117S+L149R+S214Y+V258P+A276S+H358D+A364G+S388K+D470T;
[1613] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+G394A+D470T;
[1614] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+N476D;
[1615] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L478N+R483V;
[1616] V45L+C60A+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[1617] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+V393H+D470T;
[1618] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+N395D+D470T;
[1619] A25W+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[1620] V45L+T70R+A117S+L149R+S214Q+C243L+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[1621] V45L+A117S+L149R+S214Q+V258P+A276S+H358T+A364G+S388K+D470T;
[1622] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+L478N;
[1623] V45L+C60S+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[1624] V45L+A117S+L149R+S214Q+W250Y+V258P+A276S+A364G+S388K+D470T;
[1625] V45L+A117S+L149R+S214Q+T215V+V258P+A276S+A364G+S388K+D470T+R483V;
[1626] V45L+Q61R+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[1627] V45L+A117S+L149R+G187L+S214Q+V258P+A276S+A364G+S388K+D470T;
[1628] D9E+V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T;
[1629] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G;
[1630] V45L+C69A+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[1631] V45L+T70R+A117S+L149R+C161S+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[1632] V45L+A117S+L149R+S214Q+H219I+V258P+A276S+H358D+A364G+S388K+D470T;
[1633] V45L+A117S+L149R+S214Q+V258P+A276S+S282N+A364G+S388K+D470T;
[1634] V45L+A117S+L149R+T211H+S214Q+V258P+A276S+A364G+S388K+D470T+R483V;
[1635] V45L+D95N+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S473G;
[1636] V45L+T70R+D95N+A117S+L149R+S214Q+V258P+A276S+L356M+H358D+A364G+S388K;
[1637] D11E+V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T;
[1638] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+N476N;
[1639] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+G394D+D470T;
[1640] V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T;
[1641] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+G503L;
[1642] V45L+A117S+L149R+S214Q+V258P+A276S+A286S+A364G+S388K+D470T;
[1643] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470A;
[1644] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+G394Q+D470T;
[1645] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388R+D470T;
[1646] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+L478P;
[1647] V45L+A117S+L149R+S214Q+V258P+A276S+V350L+A364G+S388K+D470T;
[1648] V45L+D113T+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T;
[1649] V45L+A117S+L149R+T180Q+S214Q+V258P+A276S+A364G+S388K+D470T;
[1650] V45L+C69V+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[1651] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+D525L;
[1652] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T;
[1653] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+V500T;
[1654] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+S389H+D470T;
[1655] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+V393R+D470T;
[1656] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+Q496R;
[1657] V45L+A117S+N127D+L149R+S214Q+V258P+A276S+A364G+S388K+D470T;
[1658] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+A499Y;
[1659] V45L+A117S+L149R+S214Q+T215V+V258P+A276S+H358D+A364G+S388K+D470T;
[1660] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T480L;
[1661] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388L+D470T;
[1662] V45L+A117S+L149R+S173Y+S214Q+V258P+A276S+A364G+S388K+D470T;
[1663] V45L+S92D+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T;
[1664] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+S389V+D470T+R483V;
[1665] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+N529T;
[1666] V45L+C60V+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[1667] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+V497E;
[1668] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+L478N;
[1669] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T;
[1670] M28P+V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T;
[1671] V45L+A117S+L149R+S214Q+V258P+A276Q+A364G+S388K+D470T;
[1672] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470V+R483V;
[1673] V45L+A117S+L149R+S214Y+V258P+A276S+A364G+S388K+D470T+R483V;
[1674] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+N395D;
[1675] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+T477K;
[1676] V45L+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K;
[1677] V45L+Q61R+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T;
[1678] V45L+A117S+L149R+S214Q+T215I+V258P+A276S+A364G+S388K+D470T;
[1679] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+Q496E;
[1680] V45L+A117S+L149R+G187K+S214Q+V258P+A276S+A364G+S388K+D470T;
[1681] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+W495I;
[1682] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+V498I;
[1683] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470K+R483V;
[1684] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+V500V;
[1685] D11E+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K;
[1686] V45L+A117S+L149R+A170S+S214Q+V258P+A276S+A364G+S388K+D470T;
[1687] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+Y391V+D470T;
[1688] V45L+A117S+L149R+S214Q+V258P+A276S+Q314A+A364G+S388K+D470T;
[1689] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+T477V;
[1690] A25W+V45L+A79C+L149R+S214E+V258P+A276S+A364G;
[1691] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394Q;
[1692] V45L+A117S+L149R+S214Q+H219V+V258P+A276S+A364G+S388K+D470T;
[1693] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+Q496Q;
[1694] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+C375A+S388K+G394A+D470T+R483V;
[1695] V45L+A117S+L149R+D192E+S214Q+V258P+A276S+H358D+A364G;
[1696] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+A472L;
[1697] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+A499Y;
[1698] V45L+A117S+L149R+S214Q+T215V+V258P+A276S+A364G+S388K+D470T;
[1699] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+Q385C+S388K+D470T;
[1700] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388A+D470T;
[1701] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388H+D470T;
[1702] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+T480N;
[1703] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+V497P;
[1704] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+A499L;
[1705] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+S501N;
[1706] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+D470T;
[1707] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+Q384A+S388K;
[1708] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+C375S+S388K+G394A+D470T+R483V;
[1709] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388L+D470T+R483V;
[1710] V45L+A79C+S92D+L149R+V258P+A276S+A364G+S388K;
[1711] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V+C540A;
[1712] V45N+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T;
[1713] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394A;
[1714] V45L+C69S+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[1715] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+V498I;
[1716] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G;
[1717] V45L+A117S+L149R+S214Q+H219I+V258P+A276S+A364G+S388K+D470T;
[1718] V45L+A117S+L149R+N163H+S214Q+V258P+A276S+A364G+S388K+D470T;
[1719] V45L+L149R+S214Q+V258P+A276S+H358D+A364G;
[1720] V45L+A117S+L149R+S214Q+V258P+A276S+Q314A+H358D+A364G+S388K;
[1721] V45L+A117S+L149R+S173Y+S214Q+V258P+A276S+H358D+A364G+S388K;
[1722] V45L+A117S+L149R+S214E+V258P+A276S+H358D+A364G+S388K;
[1723] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394D;
[1724] A25W+V45L+A79C+L149R+V258P+A276S+A364G;
[1725] V45L+L149R+S214Q+V258P+A276S+A286E+A364G+S388K;
[1726] V45L+Q61R+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K;
[1727] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+T366V+S388K;
[1728] V45L+A117S+L149R+D192E+S214Q+V258P+A276S+H358D+A364G;
[1729] V45L+A117S+L149R+T180Q+S214Q+V258P+A276S+H358D+A364G+S388K;
[1730] V45L+A117S+L149R+S214Q+T215I+V258P+A276S+H358D+A364G+S388K;
[1731] V45L+A117S+L149R+S214Q+W250Y+V258P+A276S+H358D+A364G+S388K;
[1732] V45L+L149R+S214Q+T215I+V258P+A276S+A364G+S388K;
[1733] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+N476D;
[1734] V45L+D113T+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V;
[1735] V45L+A117S+L149R+S214Q+T215K+V258P+A276S+A364G+S388K+D470T+R483V;
[1736] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K;
[1737] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+T477V;
[1738] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+L478P;
[1739] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S481A;
[1740] A25W+V45L+L149R+S214Q+V258P+A276S+A364G+S388K;
[1741] V45L+A117S+L149R+T211H+S214Q+V258P+A276S+A364G+S388K+D470T;
[1742] V45L+A117S+L149R+S214Q+T215K+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[1743] V45L+A79C+L149R+V258P+A276S+L281V+A364G;
[1744] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+R483V;
[1745] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+V500T;
[1746] V45L+A117S+L149R+S214Q+V258P+A276S+V350L+H358D+A364G+S388K;
[1747] V45L+A117S+L149R+G187K+S214Q+V258P+A276S+H358D+A364G+S388K;
[1748] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+C375L+S388K+G394A+D470T+R483V;
[1749] V45L+L149R+A170S+S214Q+V258P+A276S+A364G+S388K;
[1750] V45L+A117S+L149R+S214E+V258P+A276S+A364G+S388K+D470T;
[1751] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470V+R483V;
[1752] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+V500V;
[1753] V45L+Q61K+L149R+S214Q+V258P+A276S+A364G+S388K;
[1754] V45L+L149R+N168G+S214Q+V258P+A276S+A364G+S388K;
[1755] V45L+A117S+L149R+N163H+S214Q+V258P+A276S+H358D+A364G+S388K;
[1756] V45L+A79C+D95D+L149R+V258P+A276S+A364G+S388K;
[1757] V45L+Q77E+A79C+L149R+V258P+A276S+A364G+S388K;
[1758] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+V497W;
[1759] V45L+L149R+S214Q+V258P+A276S+S282N+A364G+S388K;
[1760] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388R;
[1761] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S481S;
[1762] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+V500T;
[1763] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V+C540L;
[1764] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V+C522S;
[1765] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+W495S;
[1766] V45L+L149R+S214Q+V258P+A276S+Q314A+A364G+S388K;
[1767] V45L+D113T+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K;
[1768] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+V497W;
[1769] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V+C540S;
[1770] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+C396S+D470T+R483V;
[1771] V45L+T70R+L149R+S214Q+V258P+A276S+A364G+S388K;
[1772] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+N474G;
[1773] V45L+A117S+L149R+S214Q+V258P+A276S+S282N+H358D+A364G+S388K;
[1774] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+Q496Q;
[1775] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+S389V+D470T;
[1776] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+C396A+D470T+R483V;
[1777] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S501E;
[1778] A25W+V45L+L149R+S214E+V258P+A276S+A364G;
[1779] V45L+L149R+S214Q+W250Y+V258P+A276S+A364G+S388K;
[1780] V45L+L149R+G187K+S214Q+V258P+A276S+A364G+S388K;
[1781] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+N476N;
[1782] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S473K;
[1783] V45L+A117S+L149R+G187L+S214Q+V258P+A276S+H358D+A364G+S388K;
[1784] C40L+V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[1785] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+Q496E;
[1786] A25W+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K;
[1787] V45L+L149R+V258P+A276S+L281V+H358T+A364G+S388K;
[1788] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388A;
[1789] V45L+A117S+L149R+N168G+S214Q+V258P+A276S+H358D+A364G+S388K;
[1790] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S389H;
[1791] M28P+V45L+L149R+S214Q+V258P+A276S+A364G+S388K;
[1792] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+T480L;
[1793] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+Q384A+S388K;
[1794] V45L+A93S+L149R+A252S+H334D;
[1795] C40A+V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[1796] V45L+L149R+G187L+S214Q+V258P+A276S+A364G+S388K;
[1797] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+Q385C+S388K;
[1798] V45L+L149R+S214Q+V258P+A276S+A286S+A364G+S388K;
[1799] V45L+S92D+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K;
[1800] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388L;
[1801] V45L+A117S+L149R+S214Q+V258P+A276S+A286E+A364G+S388K;
[1802] D9E+V45L+L149R+S214Q+V258P+A276S+A364G+S388K;
[1803] V45L+L149R+S173Y+S214Q+V258P+A276S+A364G+S388K;
[1804] V45L+A117S+L149R+A170S+S214Q+V258P+A276S+H358D+A364G+S388K;
[1805] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+Y391V;
[1806] V45L+A117S+L149R+S214Q+V258P+A276S+L281V+A364G+S388K;
[1807] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+G394D;
[1808] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+S473G;
[1809] V45L+A79C+L149R+V258P+A276S+H358T+A364G+S388K;
[1810] V45L+L149R+S214Q+V258P+A276Q+A364G+S388K;
[1811] A25W+V45L+L149R+S214E+V258P+A276S+H358T+A364G;
[1812] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+T480N;
[1813] D9E+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K;
[1814] V45L+A117S+L149R+S214Q+H219I+V258P+A276S+H358D+A364G+S388K;
[1815] C40S+V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[1816] C40V+V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[1817] A25W+V45L+L149R+S214E+V258P+A276S+A286E+A364G;
[1818] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+G394A;
[1819] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+A499L;
[1820] A25W+V45L+Q61K+L149R+S214E+V258P+A276S+A364G;
[1821] V45L+A117S+L149R+S214Q+T215V+V258P+A276S+H358D+A364G+S388K;
[1822] A25W+V45L+L149R+V258P+A276S+H358T+A364G+S388K;
[1823] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+W495E;
[1824] A25W+V45L+A79C+L149R+V258P+A276S;
[1825] V45L+L149R+S214Q+V258P+A276S+V350L+A364G+S388K;
[1826] D11E+V45L+L149R+S214Q+V258P+A276S+A364G+S388K;
[1827] V45L+L149R+H219I+V258P+A276S+H358T+A364G+S388K;
[1828] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+C396V+D470T+R483V;
[1829] V45N+L149R+S214Q+V258P+A276S+A364G+S388K;
[1830] V45L+A117S+L149R+S214Q+H219V+V258P+A276S+H358D+A364G+S388K;
[1831] V45N+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K;
[1832] V45L+S92D+L149R+S214Q+V258P+A276S+A364G+S388K;
[1833] V45L+L149R+V258P+A276S+H358T+A364G;
[1834] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+L478P;
[1835] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+S481A;
[1836] V45L+A117S+L149R+S214Q+V258P+A276S+Q314A+A364G+S388K;
[1837] A25W+V45L+L149R+T211H+S214E+V258P+A276S+A364G;
[1838] A25W+V45L+L149R+S214E+H219V+V258P+A276S+A364G;
[1839] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S389V;
[1840] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+V393H;
[1841] V45L+A117S+L149R+S214Q+V258P+A276Q+H358D+A364G+S388K;
[1842] V45L+A117S+N127D+L149R+S214Q+V258P+A276S+H358D+A364G+S388K;
[1843] V45L+L149R+W250Y+V258P+A276S+H358T+A364G+S388K;
[1844] D9E+V45L+L149R+V258P+A276S+H358T+A364G+S388K;
[1845] V45L+L149R+H219V+V258P+A276S+H358T+A364G+S388K;
[1846] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+A472L;
[1847] A25W+V45L+L149R+V258P+A276S+A364G;
[1848] V45L+A117S+L149R+G187K+S214Q+V258P+A276S+A364G+S388K;
[1849] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+L478N;
[1850] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+V393R;
[1851] V45L+A117S+L149R+S214E+V258P+A276S+A364G+S388K;
[1852] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+T366V+S388K;
[1853] V45L+A117S+L149R+S214Q+V258P+A276S+H358T+A364G+S388K;
[1854] D11E+A25W+V45L+L149R+S214E+V258P+A276S+A364G;
[1855] V45L+T70R+A117S+L149R+C161V+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[1856] V45L+A117S+L149R+T211H+S214Q+V258P+A276S+H358D+A364G+S388K;
[1857] V45L+L149R+V258P+A276S+Q314A+H358T+A364G+S388K;
[1858] D11E+V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K;
[1859] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+G394Q;
[1860] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+N395D;
[1861] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+V393H;
[1862] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+S501E;
[1863] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+S528H;
[1864] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[1865] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388L;
[1866] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+C396L+D470T+R483V;
[1867] V45L+L149R+T180Q+S214Q+V258P+A276S+A364G+S388K;
[1868] V45L+D113T+L149R+S214Q+V258P+A276S+A364G+S388K;
[1869] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+T480L;
[1870] V45L+A93S+L149R+A252S+H334D;
[1871] V45L+A93S+L149R+V234P+A252S;
[1872] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388H;
[1873] A25W+V45L+Q61R+L149R+S214E+V258P+A276S+A364G;
[1874] V45L+A117S+L149R+S214Q+T215K+V258P+A276S+H358D+A364G+S388K+V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+S389H;
[1875] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+T366I+S388K;
[1876] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+N474G;
[1877] A25W+V45L+L149R+S214E+V258P+A276S+L281V+A364G;
[1878] D9E+A25W+V45L+L149R+S214E+V258P+A276S+A364G;
[1879] V45L+A117S+L149R+S214Q+T215K+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[1880] V45L+A117S+L149R+S214Y+V258P+A276S+H358D+A364G+S388K;
[1881] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+V393R;
[1882] V45L+Q61R+L149R+V258P+A276S+H358T+A364G+S388K;
[1883] V45L+L149R+S214Q+V258P+A276S+A364G+S388K;
[1884] V45L+D113T+L149R+V258P+A276S+H358T+A364G+S388K;
[1885] V45L+A117S+L149R+S214Q+V258P+A276S+A286S+A364G+S388K;
[1886] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388R;
[1887] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+A499Y;
[1888] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+V500V;
[1889] V45L+Q61R+L149R+S214Q+V258P+A276S+A364G+S388K;
[1890] V45L+L149R+S214E+V258P+A276S+H358T+A364G;
[1891] V45L+A117S+L149R+S214Q+V258P+A276Q+A364G+S388K;
[1892] V45L+L149R+V258P+A276S+L281V+A364G;
[1893] V45L+A117S+L149R+S214Q+W250Y+V258P+A276S+A364G+S388K;
[1894] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+T480N;
[1895] V45L+A117S+L149R+G187S+S214Q+V258P+A276S+A364G+S388K;
[1896] A25W+V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K;
[1897] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K;
[1898] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+N476N;
[1899] A25W+V45L+L149R+S214E+V258P+A276Q+A364G;
[1900] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+N476D;
[1901] V45L+L149R+S214Q+V258P+A276S+L281V+A364G;
[1902] V45L+A93S+L149R+A252S+H334D+A340G;
[1903] V45L+A93S+L149R+A252S+H334D;
[1904] V45L+A93S+L149R+A252S+H334D;
[1905] V45L+L149R+A252S+H334D;
[1906] V45L+N127D+L149R+V258P+A276S+A364G+S388K;
[1907] V45L+L149R+V258P+A276S+H358T+A364G+S388K;
[1908] V45L+L149R+V258P+A276S+A364G+S388K;
[1909] D9E+V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K;
[1910] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+S481S;
[1911] V45L+L149R+N168G+V258P+A276S+A364G;
[1912] V45L+L149R+T180Q+V258P+A276S+H358T+A364G+S388K;
[1913] V45L+L149R+G187L+V258P+A276S+A364G+S388K;
[1914] V45L+L149R+W250Y+V258P+A276S+A364G+S388K;
[1915] V45L+L149R+V258P+A276S+A286E+A364G+S388K;
[1916] V45L+L149R+V258P+A276S+S282N+A364G+S388K;
[1917] A25W+V45L+L149R+V258P+A276S+A364G+S388K;
[1918] V45L+L149R+S214Q+V258P+A276S+H358T+A364G;
[1919] V45L+L149R+S173Y+V258P+A276S+A364G;
[1920] V45L+A117S+L149R+S214Q+H219V+V258P+A276S+A364G+S388K;
[1921] V45L+A93S+L149R+A252S+H334D;
[1922] V45L+A93S+L149R+A252S+H334D+A340G;
[1923] V45L+L149R+S190E+D446T+R459V;
[1924] A25W+V45L+L149R+V258P+A276S+H358T;
[1925] A25W+V45L+S92D+L149R+S214E+V258P+A276S+A364G;
[1926] A25W+V45L+L149R+S214E+V258P+A276S+V350L+A364G;
[1927] A25W+V45L+L149R+S214Q+V258P+A276S+A364G;
[1928] V45L+L149R+N168G+V258P+A276S+A364G+S388K;
[1929] V45L+A117S+L149R+V258P+A276S+A364G+S388K;
[1930] A25W+V45L+L149R+V258P+A276S+H358T+A364G;
[1931] V45L+L149R+V258P+N260H+A276S+A364G+S388K;
[1932] V45L+L149R+T215I+V258P+A276S+A364G+S388K;
[1933] A25W+V45L+L149R+V258P+A276Q+A364G;
[1934] V45L+T70R+A117S+L149R+C161L+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[1935] A25W+V45L+L149R+S214E+V258P+A276S;
[1936] V45L+A117S+L149R+S214Q+V258P+A276S+A286S+H358D+A364G+S388K;
[1937] V45L+L149R+T211H+S214Q+V258P+A276S+A364G+S388K;
[1938] V45L+Q61K+L149R+V258P+A276S+H358T+A364G;
[1939] V45L+L149R+V258P+A276S+Q314A+H358T+A364G;
[1940] V45L+L149R+T180Q+V258P+A276S+A364G+S388K;
[1941] V45L+L149R+V258P+A276S+Q314A+A364G+S388K;
[1942] A25W+V45L+L149R+V258P+A276S+A286S+A364G;
[1943] V45L+L149R+S190E+D446T;
[1944] V45L+L149R+V258P+A276S+A364G;
[1945] V45L+L149R+A170S+V258P+A276S+A364G;
[1946] V45L+L149R+V258P+A276Q+A364G;
[1947] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V+C522A;
[1948] V45L+L149R+H219I+V258P+A276S+H358T+A364G;
[1949] V45L+L149R+V258P+A276S+V350L+A364G+S388K;
[1950] D11E+V45L+L149R+V258P+A276S+A364G+S388K;
[1951] V45L+D113T+L149R+V258P+A276S+A364G+S388K;
[1952] V45L+L149R+G187K+V258P+A276S+A364G+S388K;
[1953] M28P+V45L+L149R+V258P+A276S+A364G+S388K;
[1954] V45L+Q61R+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[1955] A25W+V45L+L149R+S214Q+V258P+A276S;
[1956] V45L+A117S+L149R+S214Q+T215I+V258P+A276S+A364G+S388K;
[1957] A25W+V45L+L149R+V258P+A276S+S388K;
[1958] A25W+V45L+L149R+S214E+H219I+V258P+A276S+A364G;
[1959] V45L+A93S+L149R+V234P+A252S+H334D;
[1960] V45L+L149R+T211H+V258P+A276S+H358T+A364G+S388K;
[1961] A25W+V45L+A117S+L149R+S214E+V258P+A276S+A364G;
[1962] V45L+L149R+S173Y+V258P+A276S+A364G+S388K;
[1963] A25W+V45L+L149R+V258P+A276S+Q314A+A364G;
[1964] V45L+L149R+G187L+V258P+A276S+H358T+A364G;
[1965] V45L+L149R+T215V+V258P+A276S+H358T+A364G;
[1966] V45L+T70R+L149R+V258P+A276S+A364G+S388K;
[1967] V45L+N127D+L149R+V258P+A276S+A364G;
[1968] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+Q496R;
[1969] V45L+L149R+W250Y+V258P+A276S+A364G;
[1970] V45L+L149R+V258P+A276S+V350L+H358T+A364G;
[1971] D9E+V45L+L149R+V258P+A276S+H358T+A364G;
[1972] V45L+L149R+T211H+V258P+A276S+H358T+A364G;
[1973] A25W+V45L+L149R+W250Y+A276Q+A364G;
[1974] V45L+L149R+V258P+A276S+L281V+A364G+S388K;
[1975] V45L+L149R+V258P+A276S+S282N+H358T+A364G;
[1976] V45L+L149R+T215I+V258P+A276S+H358T+A364G;
[1977] A25W+V45L+L149R+S173Y+V258P+A276S+A364G;
[1978] V45L+Q61K+L149R+V258P+A276S+A364G+S388K;
[1979] V45L+L149R+T180Q+V258P+A276S+A364G;
[1980] V45L+A117S+L149R+A170S+S214Q+V258P+A276S+A364G+S388K;
[1981] V45L+Q61R+A117S+L149R+S214Q+V258P+A276S+A364G+S388K;
[1982] A25W+V45L+L149R+S214E+T215V+V258P+A276S+A364G;
[1983] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+V497P;
[1984] V45L+L149R+V258P+A276S+Q314A+A364G;
[1985] V45L+A117S+L149R+V258P+A276S+A364G;
[1986] V45L+A117S+L149R+V258P+A276S+H358T+A364G+S388K;
[1987] V45L+L149R+N168G+V258P+A276S+H358T+A364G+S388K;
[1988] A25W+V45L+Q61K+L149R+V258P+A276S+A364G;
[1989] V45L+L149R+S214E+V258P+A276S+L281V+A364G;
[1990] V45N+L149R+V258P+A276S+A364G+S388K;
[1991] V45L+L149R+V258P+A276S+A286E+H358T+A364G;
[1992] D9E+V45L+L149R+V258P+A276S+A364G+S388K V45L+S92D+L149R+V258P+A276S+A364G+S388K;
[1993] V45L+A117S+L149R+T180Q+S214Q+V258P+A276S+A364G+S388K;
[1994] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388H;
[1995] V45L+A117S+L149R+S214Q+T215V+V258P+A276S+A364G+S388K;
[1996] V45L+A117S+L149R+S214Q+V258P+A276S+V350L+A364G+S388K;
[1997] A25W+V45L+L149R+S214E+T215I+V258P+A276S+A364G;
[1998] V45L+N127D+L149R+V258P+A276S+H358T+A364G+S388K;
[1999] A25W+V45L+L149R+V258P+A276S+A286E+A364G;
[2000] V45L+L149R+N168G+V258P+A276S+L281V+A364G;
[2001] V45L+Q61R+L149R+V258P+A276S+H358T+A364G;
[2002] V45L+L149R+G187S+V258P+A276S+A364G+S388K;
[2003] V45L+L149R+V258P+A276S+L281V+Q314A+A364G;
[2004] V45L+L149R+V258P+A276S+L281V+H358T+A364G;
[2005] V45L+L149R+A170S+V258P+A276S+H358T+A364G;
[2006] V45L+L149R+A170S+V258P+A276S+A364G+S388K;
[2007] V45L+L149R+T215V+V258P+A276S+A364G+S388K;
[2008] V45L+L149R+V258P+A276Q+L281V+A364G;
[2009] V45L+T70R+A117S+L149R+S214Q+C243S+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[2010] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V+C522V;
[2011] A25W+V45L+L149R+V258P+A276S+Q314A;
[2012] V45L+L149R+V258P+A276Q+H358T+A364G+S388K;
[2013] A25W+V45N+L149R+S214E+V258P+A276S+A364G;
[2014] V45L+L149R+V258P+A276S+A286E+A364G;
[2015] V45L+L149R+V258P+A276S+A286S+H358T+A364G;
[2016] A25W+V45L+L149R+G187S+V258P+A276S+A364G;
[2017] V45L+L149R+T180Q+V258P+A276S+L281V+A364G;
[2018] A25W+V45L+L149R+A276Q+L281V+A364G;
[2019] V45L+S92D+L149R+V258P+A276S+L281V+A364G;
[2020] V45L+Q61R+L149R+V258P+A276S+L281V+A364G;
[2021] V45L+L149R+A170S+V258P+A276S+L281V+A364G;
[2022] D11E+A25W+V45L+L149R+V258P+A276S+A364G;
[2023] A25W+V45L+Q61R+L149R+V258P+A276S+A364G;
[2024] A25W+V45L+L149R+T215V+V258P+A276S+A364G;
[2025] D9E+V45L+L149R+V258P+A276S+L281V+A364G;
[2026] A25W+V45L+L149R+V258P+A276S+V350L+A364G;
[2027] V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+A364G+S388K;
[2028] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+Y391V;
[2029] V45L+A117S+L149R+N168G+S214Q+V258P+A276S+A364G+S388K;
[2030] V45L+D113T+A117S+L149R+S214Q+V258P+A276S+A364G+S388K;
[2031] A25W+V45L+L149R+V258P+A276S+A286E;
[2032] A25W+V45L+L149R+V258P+A276S+L281V;
[2033] A25W+V45L+D113T+L149R+V258P+A276S;
[2034] V45L+L149R+H219V+V258P+A276S+L281V+A364G;
[2035] V45L+L149R+T180Q+V258P+A276S+H358T+A364G;
[2036] V45L+L149R+T215V+V258P+A276S+L281V+A364G;
[2037] A25W+V45L+L149R+V258P+A276S+S282N+A364G;
[2038] A25W+V45L+L149R+T215I+V258P+A276S+A364G;
[2039] A25W+V45L+L149R+H219I+V258P+A276S+A364G;
[2040] V45L+A117S+L149R+V258P+A276S+L281V+A364G;
[2041] D9E+A25W+V45L+L149R+V258P+A276S+A364G;
[2042] V45L+L149R+S214Y+V258P+A276S+A364G+S388K;
[2043] A25W+V45L+L149R+T180Q+V258P+A276S+A364G;
[2044] A25W+V45L+L149R+V258P+A276S+L281V+A364G;
[2045] V45L+N127D+L149R+V258P+A276S+L281V+A364G;
[2046] V45L+L149R+S173Y+V258P+A276S+H358T+A364G;
[2047] V45L+Q61R+L149R+V258P+A276S+A364G+S388K;
[2048] M28P+V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K;
[2049] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388A;
[2050] V45N+A117S+L149R+S214Q+V258P+A276S+A364G+S388K;
[2051] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+T477K;
[2052] A25W+V45L+L149R+T180Q+V258P+A276S;
[2053] A25W+V45L+L149R+V258P+A276S+A286S;
[2054] A25W+V45L+L149R+G187S+S214E+V258P+A276S+A364G;
[2055] V45L+L149R+V258P+A276S+L281V+A286E+A364G;
[2056] A25W+V45L+L149R+W250Y+V258P+A276S+A364G;
[2057] A25W+V45L+L149R+V258P+N260H+A276S+A364G;
[2058] V45L+L149R+V258P+A276S+L281V+V350L+A364G;
[2059] A25W+V45L+L149R+A170S+V258P+A276S+A364G;
[2060] V45L+L149R+V258P+A276S+L281V+A286S+A364G;
[2061] V45L+L149R+V258P+A276S+L281V+S282N+A364G;
[2062] D11E+V45L+L149R+V258P+A276S+L281V+A364G;
[2063] V45L+Q61K+L149R+V258P+A276S+L281V+A364G;
[2064] V45L+L149R+T215I+V258P+A276S+L281V+A364G;
[2065] A25W+V45L+S92D+L149R+V258P+A276S+A364G;
[2066] V45L+L149R+S214Y+V258P+A276S+L281V+A364G;
[2067] V45L+L149R+T211H+V258P+A276S+L281V+A364G;
[2068] A25W+V45L+L149R+G187L+V258P+A276S+A364G;
[2069] V45L+S92D+L149R+V258P+A276S+H358T+A364G;
[2070] V45L+L149R+G187L+A276Q+L281V+A364G;
[2071] V45L+L149R+A276Q+L281V+V350L+A364G;
[2072] V45L+L149R+A276Q+L281V+A364G+S388K;
[2073] V45L+A117S+L149R+S214Y+V258P+A276S+A364G+S388K;
[2074] A25W+V45L+S92D+L149R+V258P+A276S;
[2075] A25W+V45L+L149R+G187L+V258P+A276S;
[2076] A25W+V45L+L149R+W250Y+V258P+A276S;
[2077] V45L+D113T+L149R+V258P+A276S+A364G;
[2078] V45L+L149R+G187K+V258P+A276S+H358T+A364G;
[2079] V45L+L149R+N163H+V258P+A276S+L281V+A364G;
[2080] A25W+V45L+T70R+L149R+V258P+A276S+A364G;
[2081] V45L+L149R+S173Y+V258P+A276S+L281V+A364G;
[2082] V45L+L149R+G187L+V258P+A276S+L281V+A364G;
[2083] V45L+L149R+G187K+V258P+A276S+L281V+A364G;
[2084] V45L+L149R+W250Y+V258P+A276S+H358T+A364G;
[2085] V45L+L149R+T211H+V258P+A276S+A364G+S388K;
[2086] V45L+L149R+N163H+V258P+A276S+A364G+S388K;
[2087] V45L+T70R+L149R+A276Q+L281V+A364G;
[2088] V45L+S92D+L149R+A276Q+L281V+A364G;
[2089] V45L+D113T+L149R+A276Q+L281V+A364G;
[2090] V45L+L149R+A276Q+L281V+Q314A+A364G;
[2091] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+S389V;
[2092] A25W+V45L+Q61K+L149R+V258P+A276S;
[2093] D9E+A25W+V45L+L149R+V258P+A276S;
[2094] V45L+T70R+L149R+V258P+A276S+A364G;
[2095] V45L+L149R+V258P+A276S+A286S+A364G+S388K;
[2096] A25W+V45L+L149R+S214Y+V258P+A276S+A364G;
[2097] A25W+V45L+D113T+L149R+V258P+A276S+A364G;
[2098] V45L+T70R+L149R+V258P+A276S+L281V+A364G;
[2099] A25W+V45L+N127D+L149R+V258P+A276S+A364G;
[2100] V45L+T70R+L149R+V258P+A276S+H358T+A364G;
[2101] V45L+L149R+N163H+V258P+A276S+A364G;
[2102] V45L+L149R+T180Q+A276Q+L281V+A364G;
[2103] V45L+L149R+A276Q+L281V+A286S+A364G;
[2104] A25W+V45L+L149R+A170S+V258P+A276S;
[2105] A25W+V45L+T70R+L149R+V258P+A276S;
[2106] A25W+V45L+L149R+S214E+V258P+A276S+A286S+A364G;
[2107] V45L+L149R+V258P+A276S+A286S+H358T+A364G+S388K;
[2108] V45L+L149R+H219I+V258P+A276S+L281V+A364G;
[2109] A25W+V45L+A117S+L149R+V258P+A276S+A364G;
[2110] A25W+V45L+L149R+N168G+V258P+A276S+A364G;
[2111] V45L+L149R+N168G+A276Q+L281V+A364G;
[2112] V45L+L149R+S173Y+A276Q+L281V+A364G;
[2113] V45L+L149R+W250Y+A276Q+L281V+A364G;
[2114] V45L+A117S+L149R+S173Y+S214Q+V258P+A276S+A364G+S388K;
[2115] A25W+V45L+L149R+A276Q+A286E+A364G;
[2116] A25W+V45L+L149R+A276Q+A364G+S388K;
[2117] V45L+N127D+L149R+V258P+A276S+H358T+A364G;
[2118] A25W+V45L+L149R+V258P+A276S;
[2119] V45L+N127D+L149R+A276Q+L281V+A364G;
[2120] V45L+L149R+A276Q+L281V+A286E+A364G;
[2121] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+V500T;
[2122] A25W+V45L+A117S+L149R+V258P+A276S;
[2123] A25W+V45L+L149R+H219V+V258P+A276S+A364G;
[2124] V45L+L149R+S173Y+V258P+A276S+H358T+A364G+S388K;
[2125] D11E+V45L+L149R+V258P+A276S+H358T+A364G;
[2126] V45L+A79C+L149R+V258P+A276S+N355G+A364G+S388K;
[2127] A24K+V45L+L149R+V258P+A276S+A364G;
[2128] V45L+L149R+V258P+A276S+S282N+A364G;
[2129] V45L+A117S+L149R+A276Q+L281V+A364G;
[2130] V45L+L149R+N260H+A276Q+L281V+A364G;
[2131] V45L+A117S+L149R+T211H+S214Q+V258P+A276S+A364G+S388K;
[2132] A25W+V45L+L149R+N168G+V258P+A276S;
[2133] A25W+V45L+L149R+G187S+V258P+A276S;
[2134] A25W+V45L+L149R+V258P+A276S+V350L;
[2135] A25W+V45L+Q61R+L149R+V258P+A276S;
[2136] A25W+V45L+L149R+G187L+S214E+V258P+A276S+A364G;
[2137] V45L+L149R+G187S+V258P+A276S+L281V+A364G;
[2138] A25W+V45L+L149R+N163H+V258P+A276S+A364G;
[2139] A25W+V45L+L149R+G187K+V258P+A276S+A364G;
[2140] V45N+L149R+V258P+A276S+L281V+A364G;
[2141] V45L+L149R+A276Q+L281V+A364G;
[2142] V45L+L149R+V258P+N260H+A276S+H358T+A364G;
[2143] V45L+L149R+A276Q+S282N+A364G;
[2144] V45L+S92D+A117S+L149R+S214Q+V258P+A276S+A364G+S388K;
[2145] A25W+V45L+L149R+V258P+A276S+S282N;
[2146] A25W+V45L+L149R+S173Y+V258P+A276S;
[2147] A25W+V45L+L149R+A276Q+A286S+A364G;
[2148] V45L+D113T+L149R+V258P+A276S+L281V+A364G;
[2149] V45L+L149R+S214Q+V258P+A276S+L281V+A364G+S388K;
[2150] V45L+D113T+L149R+V258P+A276S+H358T+A364G;
[2151] A25W+V45L+L149R+T215V+V258P+A276S;
[2152] V45L+L149R+N168G+V258P+A276S+H358T+A364G;
[2153] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+A472L;
[2154] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+S473K;
[2155] A25W+V45L+L149R+T215I+V258P+A276S;
[2156] A25W+V45L+L149R+T211H+V258P+A276S;
[2157] A25W+V45L+L149R+V258P+A276Q;
[2158] V45L+L149R+S214Q+T215V+V258P+A276S+A364G+S388K;
[2159] V45L+L149R+N163H+V258P+A276S+H358T+A364G+S388K;
[2160] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+A499L;
[2161] V45L+L149R+V258P+A276S+V350L+A364G;
[2162] V45L+A79C+A117S+L149R+V258P+A276S+A364G+S388K;
[2163] A25W+V45L+D113T+L149R+A276Q+A364G;
[2164] A25W+V45N+L149R+V258P+A276S+A364G;
[2165] V45L+T70R+L149R+A276Q+A364G;
[2166] A25W+V45L+L149R+H219I+V258P+A276S;
[2167] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+V498I;
[2168] M28P+V45L+L149R+V258P+A276S+A364G;
[2169] A25W+V45L+T70R+L149R+A276Q+A364G;
[2170] A25W+V45L+L149R+A276Q+Q314A+A364G;
[2171] V45L+L149R+A170S+V258P+A276S+H358T+A364G+S388K;
[2172] A25W+V45L+L149R+S214Y+V258P+A276S;
[2173] V45L+L149R+S214Y+V258P+A276S+H358T+A364G;
[2174] V45L+L149R+A276Q+L281V+H358T+A364G;
[2175] A25W+V45L+L149R+H219V+V258P+A276S;
[2176] V45L+A117S+L149R+N163H+S214Q+V258P+A276S+A364G+S388K;
[2177] D11E+A25W+V45L+L149R+V258P+A276S;
[2178] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+N527H;
[2179] A25W+V45L+A117S+L149R+A276Q+A364G;
[2180] V45L+L149R+V258P+L281V+A364G;
[2181] A25W+V45L+L149R+G187L+A276Q+A364G;
[2182] V45N+L149R+V258P+A276S+H358T+A364G;
[2183] V45L+A117S+L149R+S214Q+V258P+A276S+N355G+H358D+A364G+S388K+D470T+R483V;
[2184] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388H+D470T+R483V A25W+V45L+L149R+A276Q+A364G;
[2185] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+V497E;
[2186] A25W+V45L+L149R+N163H+A276Q+A364G;
[2187] A25W+V45L+L149R+S173Y+A276Q+A364G;
[2188] A25W+V45L+L149R+A276Q+S282N+A364G;
[2189] A25W+V45L+L149R+A276Q+H358T+A364G;
[2190] A25W+V45L+L149R+T180Q+A276Q+A364G;
[2191] V45L+A117S+L149R+V258P+A276S+H358T+A364G;
[2192] V45L+L149R+A276Q+Q314A+A364G;
[2193] V45L+L149R+G187K+V258P+A364G;
[2194] V45L+L149R+A276Q+A286E+A364G;
[2195] A25W+V45L+N127D+L149R+A276Q+A364G;
[2196] A25W+V45L+L149R+A170S+A276Q+A364G;
[2197] A25W+V45L+N127D+L149R+V258P+A276S;
[2198] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+T477V;
[2199] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+G503L;
[2200] A25W+M28P+V45L+L149R+V258P+A276S+A364G;
[2201] V45L+L149R+A276Q+H358T+A364G;
[2202] A25W+V45L+L149R+N168G+A276Q+A364G;
[2203] A25W+V45L+L149R+N260H+A276Q+A364G;
[2204] V45L+A117S+L149R+G187L+S214Q+V258P+A276S+A364G+S388K;
[2205] V45L+A117S+L149R+N163H+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[2206] V45L+A117S+L149R+S214Q+T215K+V258P+A276S+A364G+S388K;
[2207] A25W+V45L+L149R+G187K+V258P+A276S;
[2208] A25W+M28P+V45L+L149R+V258P+A276S;
[2209] A25W+V45N+L149R+V258P+A276S;
[2210] V45L+A117S+L149R+S214Q+V258P+A276S+N355G+H358D+A364G+S388K+D470T;
[2211] V45L+N127D+L149R+A276Q+A364G;
[2212] V45L+L149R+W250Y+A276Q+A364G;
[2213] V45L+L149R+W250Y+V258P+A364G;
[2214] V45L+L149R+N163H+A276Q+L281V+A364G;
[2215] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+Q385C+S388K;
[2216] A25W+V45L+L149R+S214E+T215K+V258P+A276S+A364G;
[2217] M28P+V45L+L149R+V258P+A276S+L281V+A364G;
[2218] V45L+L149R+A276Q+A364G+S388K;
[2219] A25W+V45L+L149R+V258P+A364G;
[2220] M28P+V45L+L149R+V258P+A276S+H358T+A364G;
[2221] V45L+A117S+L149R+S214Q+V258P+A276S+N355G+H358D+A364G+S388K;
[2222] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V+C540V;
[2223] V45L+L149R+N168G+A276Q+A364G;
[2224] V45L+A117S+L149R+A276Q+A364G;
[2225] V45L+L149R+N163H+V258P+A276S+H358T+A364G;
[2226] V45L+L149R+T215K+V258P+A276S+H358T+A364G;
[2227] A24K+V45L+L149R+A276Q+A364G;
[2228] V45L+L149R+A276Q+A286S+A364G;
[2229] V45L+L149R+V258P+A364G;
[2230] V45L+L149R+H219I+V258P+A276S+A364G+S388K;
[2231] V45L+L149R+A170S+A276Q+A364G;
[2232] V45L+L149R+T180Q+A276Q+A364G;
[2233] V45L+L149R+A276Q+V350L+A364G;
[2234] V45L+L149R+V258P+S282N+A364G;
[2235] V45L+L149R+A276Q+A364G;
[2236] V45L+L149R+A276S+A364G;
[2237] V45L+L149R+T215K+V258P+A276S+A364G+S388K;
[2238] V45L+A117S+L149R+S214Q+V258P+A276S+N355G+A364G+S388K+D470T V45L+L149R+V258P+A276S;
[2239] A25W+V45L+L149R+A276S+A364G;
[2240] V45L+L149R+G187S+V258P+A364G;
[2241] V45L+S92D+L149R+V258P+A276S+H358T+A364G+S388K;
[2242] A25W+L149R+V258P+A276S+A364G;
[2243] V45L+L149R+G187L+A276Q+A364G;
[2244] A25W+V45L+V258P+A276S+A364G;
[2245] V45L+L149R+N260H+A276Q+A364G;
[2246] V45L+L149R+W250Y+V258R+A364G;
[2247] V45L+L149R+N163H+A276Q+A364G;
[2248] V45L+S92D+L149R+A276Q+A364G;
[2249] V45L+L149R+S173Y+A276Q+A364G;
[2250] V45L+S92D+L149R+V258P+A364G;
[2251] V45L+L149R+W250Y+V258P+A276S+L281V+A364G;
[2252] V45L+L149R+L281V+A364G;
[2253] V45L+D113T+L149R+A276Q+A364G;
[2254] L149R+V258P+A276S+A364G;
[2255] V45L+L149R+G187S+V258R+A364G;
[2256] V45L+V258P+A276S+A364G;
[2257] V45L+L149R+V258R+A364G+S388K;
[2258] A25W+V45L+L149R+A364G;
[2259] V45L+L149R+G187K+V258R+A364G;
[2260] V45L+L149R+V258P;
[2261] V45L+L149R+V258R+S282N+A364G;
[2262] V45L+L149R;
[2263] V45L+L149R+V258R+L281V+A364G;
[2264] V45L+L149R+A364G;
[2265] V45L+L149R+S214Q+V258P+A276S+N355G+A364G+S388K;
[2266] V45L+S92N+L149R+V258P+A364G;
[2267] V45L+A117S+L149R+S214Q+V258P+A276S+A286E+H358D+A364G+S388K;
[2268] A25W+V45L+L149R+S214E+V258P+A276S+N355G+A364G;
[2269] V45L+L149R+G187L+V258P+A276S+A364G;
[2270] V45L+L149R+V258R+A364G;
[2271] V45L+L149R+V258P+A364G+S388K;
[2272] A25W+V45L+L149R+A276Q+V350L+A364G;
[2273] V45L+L149R+H219V+V258P+A276S+A364G+S388K;
[2274] V45L+L149R+G187K+A364G;
[2275] V45L+L149R+G187S+A364G;
[2276] V45L+A117S+L149R+S214Q+V258P+A276S+N355G+A364G+S388K;
[2277] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+Y386G+S388K+D470T+R483V;
[2278] V45L+L149R+W250Y;
[2279] V45L+S92N+L149R+V258R+A364G;
[2280] A25W+V45L+L149R+V258P+A276S+N355G+A364G;
[2281] V45L+L149R+V258P+A276S+N355G+A364G+S388K;
[2282] V45L+L149R+G187S;
[2283] V45N+L149R;
[2284] V45L+L149R+S282N;
[2285] L149R+A364G;
[2286] Y386G;
[2287] V258P+A276Q;
[2288] V258P+A276S;
[2289] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394D+D470T+R483V;
[2290] A25W+L149R;
[2291] V45L+A276S;
[2292] V45L+S92D+L149R;
[2293] A25W+A276S;
[2294] Q385C;
[2295] V45L+L149R+W250Y+A364G;
[2296] V45L+A276Q;
[2297] V45L+V258P;
[2298] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+Y386G+S388K;
[2299] A25W+V258P;
[2300] A25W+A276Q;
[2301] L149R+W250Y;
[2302] V45L+L149R+V258P+A276S+L281V+N355G+A364G;
[2303] V45L+S388K;
[2304] V45L+L149R+V258P+A276S+N355G+H358T+A364G;
[2305] V45L+A364G;
[2306] V45N+V258P;
[2307] A276S;
[2308] V258P+S388K;
[2309] A25W+V45L;
[2310] A276Q+S388K;
[2311] A276C;
[2312] A276Q;
[2313] A276F;
[2314] W250Y+A276Q;
[2315] A79C;
[2316] A276S+S388K;
[2317] A276Q+L281V;
[2318] V45L+L149R+V258P+A276S+N355G+A364G;
[2319] A276N;
[2320] W250Y+A276S;
[2321] A25W+S388K;
[2322] A276S+L281V;
[2323] G187S+A276Q;
[2324] A25W+V45L+L149R+V258P+A276S+N355G;
[2325] V45L;
[2326] S92D+A276S;
[2327] S19T;
[2328] L149R+V258R;
[2329] V45N+S388K;
[2330] A25W+V45L+S92D+L149R+A276Q+A364G;
[2331] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+S501E H358D;
[2332] A25W+A364G;
[2333] V258P+L281V;
[2334] L149R;
[2335] V45L+L149R+H219V+V258P+A276S+H358T+A364G;
[2336] A25W;
[2337] V258R+A276S;
[2338] V45N;
[2339] G187S+A276S;
[2340] G187K+A276S;
[2341] I469T;
[2342] V45L+S92D;
[2343] V45L+L281V;
[2344] V45N+W250Y;
[2345] V258R+A276Q;
[2346] V45L+V258R;
[2347] W250Y+S388K;
[2348] A25W+V45L+L149R+A276Q+N355G+A364G;
[2349] V45N+G187K;
[2350] A25W+V45L+L149R+S214E+V258P+A276S+Q314A+A364G;
[2351] S388A;
[2352] A276T;
[2353] A25W+V258R;
[2354] G187K+S388K;
[2355] A25W+S92D;
[2356] L281V+S388K;
[2357] V45N+V258R;
[2358] S388H;
[2359] S92D;
[2360] D525L;
[2361] S214Q;
[2362] L281V+A364G;
[2363] A364G;
[2364] S388L;
[2365] S388R;
[2366] S473G;
[2367] S92D+A364G;
[2368] A25W+G187S;
[2369] A25W+G187K;
[2370] W250Y+V258P;
[2371] S92D+V258P S389V;
[2372] A20H;
[2373] W495E;
[2374] G187K+W250Y;
[2375] Y386Y;
[2376] V393H;
[2377] G187L;
[2378] Q61K;
[2379] V45N+S92D;
[2380] G187S+A364G;
[2381] G187S+L281V;
[2382] G187S;
[2383] A286E;
[2384] A276Y;
[2385] V258P;
[2386] Q496E;
[2387] G394A;
[2388] V393R;
[2389] G187S+S388K;
[2390] T366V; and wherein the variant has xylanse activity and wherein the variant has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%, but less than 100% sequence identity to SEQ ID NO: 1, and wherein the variants have increased thermostability measured as increased melting temperature measured by TSA of at least 1° C. compared to the xylanase of SEQ ID NO: 1.
[2391] In one aspect, the present invention relates to xylanase variants comprises at least one of the following substitutions or combinations of substitutions:
[2392] V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+A286E+H358D+A364G+Q384A+S388K+V393H+D470T+R483V;
[2393] V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q384A+S388K+G394Q+D470T+R483V;
[2394] V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q384A+S388K+G394A+D470T+R483V;
[2395] V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q384A+S388K+V393H+D470T+R483V;
[2396] V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q384A+S388K+V393H+D470T+R483V;
[2397] V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q384A+S388K+G394A+D470T+R483V;
[2398] V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q384A+S388K+V393H+D470T+R483V;
[2399] V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q384A+S388K+G394A+D470T+R483V;
[2400] V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+A286E+H358D+A364G+Q384A+S388K+V393H+D470T+R483V;
[2401] V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q384A+S388K+V393H+D470T+R483V;
[2402] V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q384A+S388K+G394A+D470T+R483V;
[2403] V45L+A79C+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[2404] V45L+A79C+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[2405] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[2406] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[2407] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[2408] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[2409] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[2410] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[2411] V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V+L530R;
[2412] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[2413] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[2414] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[2415] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[2416] V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+L530R;
[2417] V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V+L530R;
[2418] V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V+L530R;
[2419] V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+D470T+R483V+L530R;
[2420] V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V+L530R;
[2421] V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+D470T+R483V+L530R;
[2422] V45L+A117S+L149R+G187K+S214Q+V258P+A276S+A286E+H358D+A364G+Q384A+S388K+V393H+D470T+R483V;
[2423] V45L+A117S+L149R+G187K+S214Q+V258P+A276S+A286E+H358D+A364G+Q384A+S388K+N395D+D470T+R483V;
[2424] V45L+A117S+L149R+G187K+S214E+T215I+V258P+A276S+A286E+H358D+A364G+S388K+V393H+D470T+R483V;
[2425] V45L+A117S+L149R+G187K+S214E+T215I+V258P+A276S+A286E+H358D+A364G+S388K+N395D+D470T+R483V;
[2426] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+Q385C+S388K+D470T+R483V;
[2427] V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[2428] V45L+A79C+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V;
[2429] V45L+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+D470T+R483V;
[2430] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+T366I+S388K+D470T+R483V;
[2431] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[2432] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+Q384A+S388K+D470T+L530R;
[2433] V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[2434] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[2435] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+V393H+D470T+R483V;
[2436] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394A+D470T+R483V;
[2437] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+V393H+D470T+L530R;
[2438] V45L+A117S+L149R+S214Q+V258P+A276S+A286E+H358D+A364G+S388K+D470T+R483V;
[2439] D11E+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[2440] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+C468V+D470T+R483V;
[2441] V45L+A79C+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[2442] V45L+A79C+L149R+S214E+V258P+A276S+A364G+S388K;
[2443] V45L+A117S+L149R+G187L+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[2444] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+Q384A+S388K+D470T+R483V;
[2445] V45L+A117S+L149R+G187K+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[2446] V45L+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+D470T+L530R;
[2447] V45L+A117S+L149R+S214E+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[2448] V45L+A117S+L149R+G187L+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[2449] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394Q+D470T+R483V;
[2450] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394A+D470T+L530R;
[2451] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+T366V+S388K+D470T+L530R;
[2452] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394Q+D470T+L530R;
[2453] V45L+A117S+L149R+S214Q+V258P+A276S+S282N+H358D+A364G+S388K+D470T+R483V V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+N395D+D470T+R483V;
[2454] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N476D+R483V;
[2455] V45L+A117S+L149R+S214Q+V258P+A276S+V350L+H358D+A364G+S388K+D470T+R483V;
[2456] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T477K+R483V;
[2457] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+Q496R;
[2458] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+C468A+D470T+R483V;
[2459] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+W495E;
[2460] V45L+A117S+L149R+S214Q+V258P+A276S+A286E+H358D+A364G+S388K+D470T+L530R;
[2461] V45L+A117S+L149R+G187K+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[2462] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+Y391V+D470T+R483V;
[2463] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[2464] D9E+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[2465] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T477V+R483V;
[2466] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N476N+R483V;
[2467] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+V393R+D470T+R483V;
[2468] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T480L+L530R;
[2469] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S481A+L530R;
[2470] V45L+A117S+L149R+S214Q+W250Y+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[2471] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S481S+R483V;
[2472] V45L+A117S+L149R+S173Y+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[2473] V45L+T70R+A117S+L149R+S214Q+C243V+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[2474] V45L+A117S+L149R+T180Q+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[2475] D11E+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[2476] V45L+A117S+L149R+S214E+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[2477] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N476D+L530R;
[2478] V45L+A117S+L149R+S214Q+V258P+A276S+A286S+H358D+A364G+S388K+D470T+R483V;
[2479] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+Q496Q;
[2480] V45L+A117S+L149R+S214Q+V258P+A276Q+H358D+A364G+S388K+D470T+R483V;
[2481] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+Q496E;
[2482] V45L+Q61R+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[2483] V45L+A117S+L149R+S214Q+V258P+A276S+Q314A+H358D+A364G+S388K+D470T+L530R;
[2484] V45L+A117S+L149R+S214Q+V258P+A276Q+H358D+A364G+S388K+D470T+L530R;
[2485] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L478P+R483V;
[2486] A25W+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[2487] V45L+A117S+L149R+T180Q+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[2488] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+L484K;
[2489] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N474G+L530R;
[2490] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+N395D+D470T+L530R;
[2491] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+T366V+S388K+D470T+R483V;
[2492] V45L+A117S+L149R+N168G+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[2493] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+L484S;
[2494] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[2495] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+L484D;
[2496] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+S528H;
[2497] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+S501N;
[2498] V45L+A117S+L149R+S173Y+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[2499] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+A499L;
[2500] V45L+S92D+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[2501] V45L+A117S+L149R+S214Q+V258P+A276S+Q314A+H358D+A364G+S388K+D470T+R483V;
[2502] V45L+A79C+L149R+S214Q+V258P+A276S+A364G+S388K;
[2503] V45L+A117S+L149R+S214Q+V258P+A276S+N355G+H358D+A364G+S388K+D470T+L530R;
[2504] V45L+A117S+L149R+S214Q+V258P+A276S+V350L+H358D+A364G+S388K+D470T+L530R;
[2505] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S481S+L530R;
[2506] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+Q496E+L530R;
[2507] V45L+A117S+L149R+N168G+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[2508] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+V498I+L530R;
[2509] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470A+R483V;
[2510] V45N+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[2511] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+A499Y;
[2512] V45L+A79C+L149R+V258P+A276S+Q314A+A364G+S388K;
[2513] V45L+A79C+L149R+V258P+A276S+L281V+A364G+S388K;
[2514] V45L+A117S+L149R+S214Q+V258P+A276S+A286S+H358D+A364G+S388K+D470T+L530R;
[2515] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S501N+L530R;
[2516] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N476N+L530R;
[2517] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T477V+L530R;
[2518] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388H+D470T+L530R;
[2519] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L478N+L530R;
[2520] V45L+S92D+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[2521] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+V500V+L530R;
[2522] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+V500V;
[2523] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L478P+L530R;
[2524] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+S501E;
[2525] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+D525L+L530R;
[2526] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+G526T+L530R;
[2527] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N527H+L530R;
[2528] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T477K+L530R;
[2529] M28P+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[2530] D9E+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[2531] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S501E+L530R;
[2532] V45L+A117S+L149R+S214Q+W250Y+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[2533] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+A499L+L530R;
[2534] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+A472I+L530R;
[2535] V45L+A117S+N127D+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[2536] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+V500T+L530R;
[2537] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+N527H;
[2538] V45N+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[2539] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T480N+L530R;
[2540] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+V497P;
[2541] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+V498I;
[2542] V45L+A79C+L149R+S173Y+V258P+A276S+A364G+S388K;
[2543] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T480N+R483V;
[2544] V45L+A117S+L149R+S214Q+H219V+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[2545] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388A+D470T+L530R;
[2546] M28P+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[2547] V45L+A117S+L149R+A170S+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[2548] V45L+A79C+L149R+G187K+V258P+A276S+A364G+S388K;
[2549] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S389H+D470T+L530R;
[2550] V45L+D113T+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[2551] V45L+A117S+L149R+N163H+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[2552] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388A+D470T+R483V;
[2553] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388L+D470T+R483V;
[2554] V45L+Q61R+A79C+L149R+V258P+A276S+A364G+S388K;
[2555] V45L+A79C+L149R+N168G+V258P+A276S+A364G+S388K;
[2556] V45L+A117S+L149R+T211H+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[2557] V45L+A79C+L149R+T215V+V258P+A276S+A364G+S388K;
[2558] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+V500T;
[2559] V45L+A79C+L149R+V258P+A276S+A286S+A364G+S388K;
[2560] V45L+A79C+L149R+H219V+V258P+A276S+A364G+S388K;
[2561] V45L+A79C+L149R+A170S+V258P+A276S+A364G+S388K;
[2562] V45L+D113T+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[2563] V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[2564] V45L+D95N+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394A+D470T;
[2565] V45L+A79C+L149R+V258P+A276S+A364G+S388K;
[2566] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+G394A+D470T+R483V;
[2567] V45L+A93T+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+A499Y;
[2568] V45L+A117S+L149R+S214Q+T215I+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[2569] V45L+A117S+L149R+S214Q+H219I+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[2570] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L478N;
[2571] V45L+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+D470T;
[2572] V45L+A117S+L149R+S214E+V258P+A276S+H358D+A364G+S388K+D470T;
[2573] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+C468L+D470T+R483V;
[2574] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+Q385C+S388K+D470T+L530R;
[2575] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+T366I+S388K+D470T;
[2576] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S473G;
[2577] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L478P;
[2578] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394D+D470T;
[2579] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+Q384A+S388K+D470T+R483V;
[2580] D11E+V45L+A79C+L149R+V258P+A276S+A364G+S388K;
[2581] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+L530R;
[2582] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N529T;
[2583] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394Q+D470T;
[2584] V45L+A117S+L149R+G187L+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[2585] V45L+A79C+L149R+V258P+A276S+A286E+A364G+S388K;
[2586] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+G503L;
[2587] V45L+A117S+L149R+S214Q+V258P+A276S+Q314A+H358D+A364G+S388K+D470T;
[2588] V45L+A117S+L149R+S214Q+V258P+A276S+V350L+H358D+A364G+S388K+D470T;
[2589] V45L+A117S+L149R+G187K+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[2590] V45L+A117S+L149R+S214Q+W250Y+V258P+A276S+H358D+A364G+S388K+D470T;
[2591] V45L+A117S+L149R+S214Q+V258P+A276S+A286E+H358D+A364G+S388K+D470T;
[2592] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+Q384A+S388K+D470T;
[2593] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388R+D470T;
[2594] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S528H, V45L+A117S+L149R+S214Q+T215V+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[2595] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+Q496R;
[2596] V45L+A117S+L149R+N163H+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[2597] V45L+A117S+L149R+S214Q+V258P+A276S+S282N+H358D+A364G+S388K+D470T;
[2598] V45L+A117S+L149R+S214Q+V258P+A276Q+H358D+A364G+S388K+D470T;
[2599] D11E+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[2600] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+T366V+S388K+D470T;
[2601] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S473K;
[2602] V45L+A79C+L149R+T180Q+V258P+A276S+A364G+S388K;
[2603] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S481A+R483V;
[2604] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388R+D470T+V45L+A117S+L149R+S214Q+V258P+A276S+Q314A+A364G+S388K+D470T+R483V;
[2605] V45L+S92D+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[2606] V45L+A117S+L149R+S214Q+V258P+N260H+A276S+H358D+A364G+S388K+D470T;
[2607] V45L+A117S+L149R+G187S+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[2608] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T477K;
[2609] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N474G;
[2610] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+N395D+D470T;
[2611] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S501N;
[2612] V45L+A117S+N127D+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[2613] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+V393R+D470T;
[2614] V45L+A117S+L149R+S173Y+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[2615] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388H+D470T;
[2616] V45L+A117S+L149R+S214Q+T215V+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[2617] V45L+A117S+L149R+G187S+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[2618] V45L+A117S+L149R+T211H+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[2619] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T480N;
[2620] V45L+A117S+L149R+N168G+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[2621] V45L+A79C+L149R+H219I+V258P+A276S+A364G+S388K;
[2622] V45L+L149R+S214E+V258P+A276S+H358D+A364G+D470T;
[2623] V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+V45L+D113T+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[2624] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+T366V+S388K+D470T+R483V;
[2625] V45L+A117S+L149R+S214Q+V258P+A276S+H358T+A364G+S388K+D470T+R483V;
[2626] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+V393R+D470T+R483V;
[2627] V45N+A79C+L149R+V258P+A276S+A364G+S388K;
[2628] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+Q496Q;
[2629] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+G394Q+D470T+R483V;
[2630] V45L+A79C+L149R+V258P+A276S+V350L+A364G+S388K;
[2631] V45L+L149R+S214E+V258P+A276S+H358D+A364G+D470T;
[2632] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+T366I+S388K+D470T+R483V;
[2633] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+G526T;
[2634] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L484S;
[2635] V45L+A79C+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K;
[2636] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+A499L;
[2637] V45L+A117S+L149R+S214Q+V258P+A276S+H358T+A364G+S388K+D470T+L530R;
[2638] V45L+A79C+D113T+L149R+V258P+A276S+A364G+S388K;
[2639] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+D525L;
[2640] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+V498I;
[2641] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388L+D470T;
[2642] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V;
[2643] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S528H+L530R;
[2644] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+N476D+R483V;
[2645] D9E+V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V;
[2646] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S501E;
[2647] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S481A;
[2648] V45L+A117S+L149R+S214Q+H219V+V258P+A276S+H358D+A364G+S388K+D470T;
[2649] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S481S;
[2650] V45L+A117S+L149R+G187K+S214Q+V258P+A276S+A364G+S388K+D470T+R483V;
[2651] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+N395D+D470T+R483V;
[2652] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+I469T+D470T+R483V;
[2653] V45L+A79C+N127D+L149R+V258P+A276S+A364G+S388K;
[2654] D9E+V45L+A79C+L149R+V258P+A276S+A364G+S388K;
[2655] V45L+L149R+S214E+V258P+A276S+H358D+A364G+D470T;
[2656] V45L+A117S+L149R+G187L+S214Q+V258P+A276S+A364G+S388K+D470T+R483V;
[2657] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N529T+L530R;
[2658] V45L+A79C+L149R+W250Y+V258P+A276S+A364G+S388K;
[2659] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+V497P;
[2660] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N527H;
[2661] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+Q496Q;
[2662] V45L+A117S+L149R+N168G+S214Q+V258P+A276S+A364G+S388K+D470T+R483V;
[2663] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+N476N+V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+T477V+R483V;
[2664] V45L+A117S+L149R+S214Q+V258P+A276S+V350L+A364G+S388K+D470T+R483V;
[2665] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+L478N+R483V;
[2666] V45L+A117S+L149R+S214E+V258P+A276S+A364G+S388K+D470T+R483V;
[2667] M28P+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[2668] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+V393H+D470T+R483V;
[2669] V45L+Q61R+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V;
[2670] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+V497P;
[2671] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+V498I;
[2672] V45L+A117S+L149R+S214Q+V258P+A276S+S282N+H358D+A364G+S388K+D470T+L530R;
[2673] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+C375V+S388K+G394A+D470T+R483V;
[2674] V45L+A117S+L149R+S214Q+V258P+A276S+A286E+A364G+S388K+D470T+R483V;
[2675] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388R+D470T+R483V;
[2676] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470A+R483V;
[2677] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+T477K+R483V;
[2678] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+Q496E;
[2679] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+Q496R;
[2680] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+A499L;
[2681] V45L+L149R+S214E+V258P+A276S+H358D+A364G+D470T;
[2682] V45L+L149R+S214E+V258P+A276S+H358D+A364G+D470T;
[2683] V45L+A117S+L149R+S214Q+T215I+V258P+A276S+H358D+A364G+S388K+V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+C468S+D470T+R483V;
[2684] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+Y391V+D470T+R483V;
[2685] V45L+A117S+L149R+S214Q+V258P+A276Q+A364G+S388K+D470T+R483V;
[2686] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+G503L+L530R;
[2687] V45L+A117S+L149R+S214Q+H219I+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[2688] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N476D;
[2689] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+V393H+D470T;
[2690] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V;
[2691] V45L+A117S+L149R+S214Q+V258P+A276S+A286S+A364G+S388K+D470T+R483V;
[2692] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+S501E;
[2693] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+N529T;
[2694] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+S501N;
[2695] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[2696] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+S481S+R483V;
[2697] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+L478P+R483V;
[2698] D11E+V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V;
[2699] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T477V;
[2700] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+V497P+L530R;
[2701] V45L+A117S+L149R+T211H+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[2702] V45L+A117S+L149R+S214Y+V258P+A276S+H358D+A364G+S388K+D470T+V45L+A117S+L149R+S214Q+W250Y+V258P+A276S+A364G+S388K+D470T+R483V;
[2703] V45L+S92D+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V;
[2704] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+N527H;
[2705] V45N+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V;
[2706] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+Q385C+S388K+D470T;
[2707] V45L+A117S+L149R+S173Y+S214Q+V258P+A276S+A364G+S388K+D470T+R483V;
[2708] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388H+D470T+R483V;
[2709] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+S389H+D470T+R483V;
[2710] V45L+A117S+L149R+S214Q+H219V+V258P+A276S+A364G+S388K+D470T+R483V;
[2711] V45L+A79C+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T;
[2712] V45L+A117S+L149R+S214Q+T215I+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[2713] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+Q496E;
[2714] V45L+A117S+L149R+A170S+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[2715] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S389V+D470T+R483V;
[2716] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S389V+D470T+L530R;
[2717] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388A+D470T;
[2718] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S389V+D470T;
[2719] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[2720] V45L+A117S+L149R+S214Q+H219I+V258P+A276S+A364G+S388K+D470T+R483V;
[2721] V45L+A79C+L149R+N163H+V258P+A276S+A364G+S388K;
[2722] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+A499Y;
[2723] V45L+A117S+L149R+S214Q+V258P+A276S+L281V+A364G+S388K+D470T+R483V;
[2724] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+V500T;
[2725] V45L+A117S+L149R+T180Q+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[2726] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+V500V;
[2727] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+G526T;
[2728] V45L+C60L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[2729] V45L+C69L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[2730] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388A+D470T+R483V;
[2731] V45L+A117S+L149R+S214Q+V258P+A276S+A286S+H358D+A364G+S388K+D470T;
[2732] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+V497D;
[2733] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470A+L530R;
[2734] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+D525L;
[2735] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N476N;
[2736] V45L+A117S+L149R+S214Q+V258P+A276S+L281V+A364G+S388K+D470T;
[2737] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+Q384A+S388K+D470T;
[2738] V45L+A117S+L149R+S214Q+V258P+A276S+A286E+A364G+S388K+D470T;
[2739] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+T477K;
[2740] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S389H+D470T;
[2741] V45L+A117S+L149R+S214Y+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[2742] V45L+A117S+L149R+S214Y+V258P+A276S+H358D+A364G+S388K+D470T;
[2743] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+G394A+D470T;
[2744] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+N476D;
[2745] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L478N+R483V;
[2746] V45L+C60A+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[2747] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+V393H+D470T;
[2748] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+N395D+D470T;
[2749] A25W+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[2750] V45L+T70R+A117S+L149R+S214Q+C243L+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[2751] V45L+A117S+L149R+S214Q+V258P+A276S+H358T+A364G+S388K+D470T;
[2752] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+L478N;
[2753] V45L+C60S+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[2754] V45L+A117S+L149R+S214Q+W250Y+V258P+A276S+A364G+S388K+D470T;
[2755] V45L+A117S+L149R+S214Q+T215V+V258P+A276S+A364G+S388K+D470T+R483V;
[2756] V45L+Q61R+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[2757] V45L+A117S+L149R+G187L+S214Q+V258P+A276S+A364G+S388K+D470T;
[2758] D9E+V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T;
[2759] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G;
[2760] V45L+C69A+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[2761] V45L+T70R+A117S+L149R+C161S+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[2762] V45L+A117S+L149R+S214Q+H219I+V258P+A276S+H358D+A364G+S388K+D470T;
[2763] V45L+A117S+L149R+S214Q+V258P+A276S+S282N+A364G+S388K+D470T;
[2764] V45L+A117S+L149R+T211H+S214Q+V258P+A276S+A364G+S388K+D470T+R483V;
[2765] V45L+D95N+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S473G;
[2766] V45L+T70R+D95N+A117S+L149R+S214Q+V258P+A276S+L356M+H358D+A364G+S388K;
[2767] D11E+V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T;
[2768] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+N476N;
[2769] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+G394D+D470T;
[2770] V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T;
[2771] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+G503L;
[2772] V45L+A117S+L149R+S214Q+V258P+A276S+A286S+A364G+S388K+D470T;
[2773] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470A;
[2774] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+G394Q+D470T;
[2775] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388R+D470T;
[2776] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+L478P;
[2777] V45L+A117S+L149R+S214Q+V258P+A276S+V350L+A364G+S388K+D470T;
[2778] V45L+D113T+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T;
[2779] V45L+A117S+L149R+T180Q+S214Q+V258P+A276S+A364G+S388K+D470T;
[2780] V45L+C69V+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[2781] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+D525L;
[2782] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T;
[2783] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+V500T;
[2784] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+S389H+D470T;
[2785] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+V393R+D470T;
[2786] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+Q496R;
[2787] V45L+A117S+N127D+L149R+S214Q+V258P+A276S+A364G+S388K+D470T;
[2788] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+A499Y;
[2789] V45L+A117S+L149R+S214Q+T215V+V258P+A276S+H358D+A364G+S388K+D470T;
[2790] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T480L;
[2791] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388L+D470T;
[2792] V45L+A117S+L149R+S173Y+S214Q+V258P+A276S+A364G+S388K+D470T;
[2793] V45L+S92D+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T;
[2794] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+S389V+D470T+R483V;
[2795] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+N529T;
[2796] V45L+C60V+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[2797] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+V497E;
[2798] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+L478N;
[2799] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T;
[2800] M28P+V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T;
[2801] V45L+A117S+L149R+S214Q+V258P+A276Q+A364G+S388K+D470T;
[2802] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470V+R483V;
[2803] V45L+A117S+L149R+S214Y+V258P+A276S+A364G+S388K+D470T+R483V;
[2804] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+N395D;
[2805] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+T477K;
[2806] V45L+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K;
[2807] V45L+Q61R+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T;
[2808] V45L+A117S+L149R+S214Q+T215I+V258P+A276S+A364G+S388K+D470T;
[2809] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+Q496E;
[2810] V45L+A117S+L149R+G187K+S214Q+V258P+A276S+A364G+S388K+D470T;
[2811] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+W495I;
[2812] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+V498I;
[2813] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470K+R483V;
[2814] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+V500V;
[2815] D11E+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K;
[2816] V45L+A117S+L149R+A170S+S214Q+V258P+A276S+A364G+S388K+D470T;
[2817] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+Y391V+D470T;
[2818] V45L+A117S+L149R+S214Q+V258P+A276S+Q314A+A364G+S388K+D470T;
[2819] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+T477V;
[2820] A25W+V45L+A79C+L149R+S214E+V258P+A276S+A364G;
[2821] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394Q;
[2822] V45L+A117S+L149R+S214Q+H219V+V258P+A276S+A364G+S388K+D470T;
[2823] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+Q496Q;
[2824] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+C375A+S388K+G394A+D470T+R483V;
[2825] V45L+A117S+L149R+D192E+S214Q+V258P+A276S+H358D+A364G;
[2826] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+A472L;
[2827] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+A499Y;
[2828] V45L+A117S+L149R+S214Q+T215V+V258P+A276S+A364G+S388K+D470T;
[2829] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+Q385C+S388K+D470T;
[2830] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388A+D470T;
[2831] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388H+D470T;
[2832] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+T480N;
[2833] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+V497P;
[2834] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+A499L;
[2835] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+S501N;
[2836] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+D470T;
[2837] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+Q384A+S388K;
[2838] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+C375S+S388K+G394A+D470T+R483V;
[2839] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388L+D470T+R483V;
[2840] V45L+A79C+S92D+L149R+V258P+A276S+A364G+S388K;
[2841] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V+C540A;
[2842] V45N+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T;
[2843] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394A;
[2844] V45L+C69S+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[2845] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+V498I;
[2846] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G;
[2847] V45L+A117S+L149R+S214Q+H219I+V258P+A276S+A364G+S388K+D470T;
[2848] V45L+A117S+L149R+N163H+S214Q+V258P+A276S+A364G+S388K+D470T;
[2849] V45L+L149R+S214Q+V258P+A276S+H358D+A364G;
[2850] V45L+A117S+L149R+S214Q+V258P+A276S+Q314A+H358D+A364G+S388K;
[2851] V45L+A117S+L149R+S173Y+S214Q+V258P+A276S+H358D+A364G+S388K;
[2852] V45L+A117S+L149R+S214E+V258P+A276S+H358D+A364G+S388K;
[2853] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394D;
[2854] A25W+V45L+A79C+L149R+V258P+A276S+A364G;
[2855] V45L+L149R+S214Q+V258P+A276S+A286E+A364G+S388K;
[2856] V45L+Q61R+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K;
[2857] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+T366V+S388K;
[2858] V45L+A117S+L149R+D192E+S214Q+V258P+A276S+H358D+A364G;
[2859] V45L+A117S+L149R+T180Q+S214Q+V258P+A276S+H358D+A364G+S388K;
[2860] V45L+A117S+L149R+S214Q+T215I+V258P+A276S+H358D+A364G+S388K;
[2861] V45L+A117S+L149R+S214Q+W250Y+V258P+A276S+H358D+A364G+S388K;
[2862] V45L+L149R+S214Q+T215I+V258P+A276S+A364G+S388K;
[2863] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+N476D;
[2864] V45L+D113T+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V;
[2865] V45L+A117S+L149R+S214Q+T215K+V258P+A276S+A364G+S388K+D470T+R483V;
[2866] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K;
[2867] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+T477V;
[2868] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+L478P;
[2869] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S481A;
[2870] A25W+V45L+L149R+S214Q+V258P+A276S+A364G+S388K;
[2871] V45L+A117S+L149R+T211H+S214Q+V258P+A276S+A364G+S388K+D470T;
[2872] V45L+A117S+L149R+S214Q+T215K+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[2873] V45L+A79C+L149R+V258P+A276S+L281V+A364G;
[2874] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+R483V;
[2875] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+V500T;
[2876] V45L+A117S+L149R+S214Q+V258P+A276S+V350L+H358D+A364G+S388K;
[2877] V45L+A117S+L149R+G187K+S214Q+V258P+A276S+H358D+A364G+S388K;
[2878] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+C375L+S388K+G394A+D470T+R483V;
[2879] V45L+L149R+A170S+S214Q+V258P+A276S+A364G+S388K;
[2880] V45L+A117S+L149R+S214E+V258P+A276S+A364G+S388K+D470T;
[2881] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470V+R483V;
[2882] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+V500V;
[2883] V45L+Q61K+L149R+S214Q+V258P+A276S+A364G+S388K;
[2884] V45L+L149R+N168G+S214Q+V258P+A276S+A364G+S388K;
[2885] V45L+A117S+L149R+N163H+S214Q+V258P+A276S+H358D+A364G+S388K;
[2886] V45L+A79C+D95D+L149R+V258P+A276S+A364G+S388K;
[2887] V45L+Q77E+A79C+L149R+V258P+A276S+A364G+S388K;
[2888] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+V497W;
[2889] V45L+L149R+S214Q+V258P+A276S+S282N+A364G+S388K;
[2890] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388R;
[2891] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S481S;
[2892] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+V500T;
[2893] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V+C540L;
[2894] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V+C522S;
[2895] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+W495S;
[2896] V45L+L149R+S214Q+V258P+A276S+Q314A+A364G+S388K;
[2897] V45L+D113T+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K;
[2898] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+V497W;
[2899] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V+C540S;
[2900] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+C396S+D470T+R483V;
[2901] V45L+T70R+L149R+S214Q+V258P+A276S+A364G+S388K;
[2902] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+N474G;
[2903] V45L+A117S+L149R+S214Q+V258P+A276S+S282N+H358D+A364G+S388K;
[2904] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+Q496Q;
[2905] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+S389V+D470T;
[2906] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+C396A+D470T+R483V;
[2907] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S501E;
[2908] A25W+V45L+L149R+S214E+V258P+A276S+A364G;
[2909] V45L+L149R+S214Q+W250Y+V258P+A276S+A364G+S388K;
[2910] V45L+L149R+G187K+S214Q+V258P+A276S+A364G+S388K;
[2911] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+N476N;
[2912] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S473K;
[2913] V45L+A117S+L149R+G187L+S214Q+V258P+A276S+H358D+A364G+S388K;
[2914] C40L+V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[2915] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+Q496E;
[2916] A25W+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K;
[2917] V45L+L149R+V258P+A276S+L281V+H358T+A364G+S388K;
[2918] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388A;
[2919] V45L+A117S+L149R+N168G+S214Q+V258P+A276S+H358D+A364G+S388K;
[2920] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S389H;
[2921] M28P+V45L+L149R+S214Q+V258P+A276S+A364G+S388K;
[2922] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+T480L;
[2923] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+Q384A+S388K;
[2924] V45L+A93S+L149R+A252S+H334D;
[2925] C40A+V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[2926] V45L+L149R+G187L+S214Q+V258P+A276S+A364G+S388K;
[2927] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+Q385C+S388K;
[2928] V45L+L149R+S214Q+V258P+A276S+A286S+A364G+S388K;
[2929] V45L+S92D+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K;
[2930] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388L;
[2931] V45L+A117S+L149R+S214Q+V258P+A276S+A286E+A364G+S388K;
[2932] D9E+V45L+L149R+S214Q+V258P+A276S+A364G+S388K;
[2933] V45L+L149R+S173Y+S214Q+V258P+A276S+A364G+S388K;
[2934] V45L+A117S+L149R+A170S+S214Q+V258P+A276S+H358D+A364G+S388K;
[2935] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+Y391V;
[2936] V45L+A117S+L149R+S214Q+V258P+A276S+L281V+A364G+S388K;
[2937] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+G394D;
[2938] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+S473G;
[2939] V45L+A79C+L149R+V258P+A276S+H358T+A364G+S388K;
[2940] V45L+L149R+S214Q+V258P+A276Q+A364G+S388K;
[2941] A25W+V45L+L149R+S214E+V258P+A276S+H358T+A364G;
[2942] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+T480N;
[2943] D9E+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K;
[2944] V45L+A117S+L149R+S214Q+H219I+V258P+A276S+H358D+A364G+S388K;
[2945] C40S+V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[2946] C40V+V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[2947] A25W+V45L+L149R+S214E+V258P+A276S+A286E+A364G;
[2948] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+G394A;
[2949] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+A499L;
[2950] A25W+V45L+Q61K+L149R+S214E+V258P+A276S+A364G;
[2951] V45L+A117S+L149R+S214Q+T215V+V258P+A276S+H358D+A364G+S388K;
[2952] A25W+V45L+L149R+V258P+A276S+H358T+A364G+S388K;
[2953] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+W495E A25W+V45L+A79C+L149R+V258P+A276S;
[2954] V45L+L149R+S214Q+V258P+A276S+V350L+A364G+S388K;
[2955] D11E+V45L+L149R+S214Q+V258P+A276S+A364G+S388K;
[2956] V45L+L149R+H219I+V258P+A276S+H358T+A364G+S388K;
[2957] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+C396V+D470T+R483V;
[2958] V45N+L149R+S214Q+V258P+A276S+A364G+S388K;
[2959] V45L+A117S+L149R+S214Q+H219V+V258P+A276S+H358D+A364G+S388K;
[2960] V45N+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K;
[2961] V45L+S92D+L149R+S214Q+V258P+A276S+A364G+S388K;
[2962] V45L+L149R+V258P+A276S+H358T+A364G;
[2963] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+L478P;
[2964] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+S481A;
[2965] V45L+A117S+L149R+S214Q+V258P+A276S+Q314A+A364G+S388K;
[2966] A25W+V45L+L149R+T211H+S214E+V258P+A276S+A364G;
[2967] A25W+V45L+L149R+S214E+H219V+V258P+A276S+A364G;
[2968] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S389V;
[2969] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+V393H;
[2970] V45L+A117S+L149R+S214Q+V258P+A276Q+H358D+A364G+S388K;
[2971] V45L+A117S+N127D+L149R+S214Q+V258P+A276S+H358D+A364G+S388K;
[2972] V45L+L149R+W250Y+V258P+A276S+H358T+A364G+S388K;
[2973] D9E+V45L+L149R+V258P+A276S+H358T+A364G+S388K;
[2974] V45L+L149R+H219V+V258P+A276S+H358T+A364G+S388K;
[2975] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+A472L;
[2976] A25W+V45L+L149R+V258P+A276S+A364G;
[2977] V45L+A117S+L149R+G187K+S214Q+V258P+A276S+A364G+S388K;
[2978] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+L478N;
[2979] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+V393R;
[2980] V45L+A117S+L149R+S214E+V258P+A276S+A364G+S388K;
[2981] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+T366V+S388K;
[2982] V45L+A117S+L149R+S214Q+V258P+A276S+H358T+A364G+S388K;
[2983] D11E+A25W+V45L+L149R+S214E+V258P+A276S+A364G;
[2984] V45L+T70R+A117S+L149R+C161V+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[2985] V45L+A117S+L149R+T211H+S214Q+V258P+A276S+H358D+A364G+S388K;
[2986] V45L+L149R+V258P+A276S+Q314A+H358T+A364G+S388K;
[2987] D11E+V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K;
[2988] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+G394Q;
[2989] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+N395D;
[2990] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+V393H;
[2991] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+S501E;
[2992] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+S528H;
[2993] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[2994] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388L;
[2995] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+C396L+D470T+R483V;
[2996] V45L+L149R+T180Q+S214Q+V258P+A276S+A364G+S388K;
[2997] V45L+D113T+L149R+S214Q+V258P+A276S+A364G+S388K;
[2998] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+T480L;
[2999] V45L+A93S+L149R+A252S+H334D;
[3000] V45L+A93S+L149R+V234P+A252S;
[3001] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388H;
[3002] A25W+V45L+Q61R+L149R+S214E+V258P+A276S+A364G;
[3003] V45L+A117S+L149R+S214Q+T215K+V258P+A276S+H358D+A364G+S388K+D470T;
[3004] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+S389H;
[3005] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+T366I+S388K;
[3006] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+N474G;
[3007] A25W+V45L+L149R+S214E+V258P+A276S+L281V+A364G;
[3008] D9E+A25W+V45L+L149R+S214E+V258P+A276S+A364G;
[3009] V45L+A117S+L149R+S214Q+T215K+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[3010] V45L+A117S+L149R+S214Y+V258P+A276S+H358D+A364G+S388K;
[3011] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+V393R;
[3012] V45L+Q61R+L149R+V258P+A276S+H358T+A364G+S388K;
[3013] V45L+L149R+S214Q+V258P+A276S+A364G+S388K;
[3014] V45L+D113T+L149R+V258P+A276S+H358T+A364G+S388K;
[3015] V45L+A117S+L149R+S214Q+V258P+A276S+A286S+A364G+S388K;
[3016] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388R;
[3017] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+A499Y;
[3018] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+V500V;
[3019] V45L+Q61R+L149R+S214Q+V258P+A276S+A364G+S388K;
[3020] V45L+L149R+S214E+V258P+A276S+H358T+A364G;
[3021] V45L+A117S+L149R+S214Q+V258P+A276Q+A364G+S388K;
[3022] V45L+L149R+V258P+A276S+L281V+A364G;
[3023] V45L+A117S+L149R+S214Q+W250Y+V258P+A276S+A364G+S388K;
[3024] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+T480N;
[3025] V45L+A117S+L149R+G187S+S214Q+V258P+A276S+A364G+S388K;
[3026] A25W+V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K;
[3027] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K;
[3028] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+N476N;
[3029] A25W+V45L+L149R+S214E+V258P+A276Q+A364G;
[3030] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+N476D;
[3031] V45L+L149R+S214Q+V258P+A276S+L281V+A364G;
[3032] V45L+A93S+L149R+A252S+H334D+A340G;
[3033] V45L+A93S+L149R+A252S+H334D;
[3034] V45L+A93S+L149R+A252S+H334D;
[3035] V45L+L149R+A252S+H334D;
[3036] V45L+N127D+L149R+V258P+A276S+A364G+S388K;
[3037] V45L+L149R+V258P+A276S+H358T+A364G+S388K;
[3038] V45L+L149R+V258P+A276S+A364G+S388K;
[3039] D9E+V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K;
[3040] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+S481S;
[3041] V45L+L149R+N168G+V258P+A276S+A364G;
[3042] V45L+L149R+T180Q+V258P+A276S+H358T+A364G+S388K;
[3043] V45L+L149R+G187L+V258P+A276S+A364G+S388K;
[3044] V45L+L149R+W250Y+V258P+A276S+A364G+S388K;
[3045] V45L+L149R+V258P+A276S+A286E+A364G+S388K;
[3046] V45L+L149R+V258P+A276S+S282N+A364G+S388K;
[3047] A25W+V45L+L149R+V258P+A276S+A364G+S388K;
[3048] V45L+L149R+S214Q+V258P+A276S+H358T+A364G;
[3049] V45L+L149R+S173Y+V258P+A276S+A364G;
[3050] V45L+A117S+L149R+S214Q+H219V+V258P+A276S+A364G+S388K;
[3051] V45L+A93S+L149R+A252S+H334D;
[3052] V45L+A93S+L149R+A252S+H334D+A340G;
[3053] V45L+L149R+S190E+D446T+R459V;
[3054] A25W+V45L+L149R+V258P+A276S+H358T;
[3055] A25W+V45L+S92D+L149R+S214E+V258P+A276S+A364G;
[3056] A25W+V45L+L149R+S214E+V258P+A276S+V350L+A364G;
[3057] A25W+V45L+L149R+S214Q+V258P+A276S+A364G;
[3058] V45L+L149R+N168G+V258P+A276S+A364G+S388K;
[3059] V45L+A117S+L149R+V258P+A276S+A364G+S388K;
[3060] A25W+V45L+L149R+V258P+A276S+H358T+A364G;
[3061] V45L+L149R+V258P+N260H+A276S+A364G+S388K;
[3062] V45L+L149R+T215I+V258P+A276S+A364G+S388K;
[3063] A25W+V45L+L149R+V258P+A276Q+A364G;
[3064] V45L+T70R+A117S+L149R+C161L+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[3065] A25W+V45L+L149R+S214E+V258P+A276S;
[3066] V45L+A117S+L149R+S214Q+V258P+A276S+A286S+H358D+A364G+S388K;
[3067] V45L+L149R+T211H+S214Q+V258P+A276S+A364G+S388K;
[3068] V45L+Q61K+L149R+V258P+A276S+H358T+A364G;
[3069] V45L+L149R+V258P+A276S+Q314A+H358T+A364G;
[3070] V45L+L149R+T180Q+V258P+A276S+A364G+S388K;
[3071] V45L+L149R+V258P+A276S+Q314A+A364G+S388K;
[3072] A25W+V45L+L149R+V258P+A276S+A286S+A364G;
[3073] V45L+L149R+S190E+D446T;
[3074] V45L+L149R+V258P+A276S+A364G;
[3075] V45L+L149R+A170S+V258P+A276S+A364G;
[3076] V45L+L149R+V258P+A276Q+A364G;
[3077] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V+C522A;
[3078] V45L+L149R+H219I+V258P+A276S+H358T+A364G;
[3079] V45L+L149R+V258P+A276S+V350L+A364G+S388K;
[3080] D11E+V45L+L149R+V258P+A276S+A364G+S388K;
[3081] V45L+D113T+L149R+V258P+A276S+A364G+S388K;
[3082] V45L+L149R+G187K+V258P+A276S+A364G+S388K;
[3083] M28P+V45L+L149R+V258P+A276S+A364G+S388K;
[3084] V45L+Q61R+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[3085] A25W+V45L+L149R+S214Q+V258P+A276S;
[3086] V45L+A117S+L149R+S214Q+T215I+V258P+A276S+A364G+S388K;
[3087] A25W+V45L+L149R+V258P+A276S+S388K;
[3088] A25W+V45L+L149R+S214E+H219I+V258P+A276S+A364G;
[3089] V45L+A93S+L149R+V234P+A252S+H334D;
[3090] V45L+L149R+T211H+V258P+A276S+H358T+A364G+S388K;
[3091] A25W+V45L+A117S+L149R+S214E+V258P+A276S+A364G;
[3092] V45L+L149R+S173Y+V258P+A276S+A364G+S388K;
[3093] A25W+V45L+L149R+V258P+A276S+Q314A+A364G;
[3094] V45L+L149R+G187L+V258P+A276S+H358T+A364G;
[3095] V45L+L149R+T215V+V258P+A276S+H358T+A364G;
[3096] V45L+T70R+L149R+V258P+A276S+A364G+S388K;
[3097] V45L+N127D+L149R+V258P+A276S+A364G;
[3098] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+Q496R;
[3099] V45L+L149R+W250Y+V258P+A276S+A364G;
[3100] V45L+L149R+V258P+A276S+V350L+H358T+A364G;
[3101] D9E+V45L+L149R+V258P+A276S+H358T+A364G;
[3102] V45L+L149R+T211H+V258P+A276S+H358T+A364G;
[3103] A25W+V45L+L149R+W250Y+A276Q+A364G;
[3104] V45L+L149R+V258P+A276S+L281V+A364G+S388K;
[3105] V45L+L149R+V258P+A276S+S282N+H358T+A364G;
[3106] V45L+L149R+T215I+V258P+A276S+H358T+A364G;
[3107] A25W+V45L+L149R+S173Y+V258P+A276S+A364G;
[3108] V45L+Q61K+L149R+V258P+A276S+A364G+S388K;
[3109] V45L+L149R+T180Q+V258P+A276S+A364G;
[3110] V45L+A117S+L149R+A170S+S214Q+V258P+A276S+A364G+S388K;
[3111] V45L+Q61R+A117S+L149R+S214Q+V258P+A276S+A364G+S388K;
[3112] A25W+V45L+L149R+S214E+T215V+V258P+A276S+A364G;
[3113] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+V497P;
[3114] V45L+L149R+V258P+A276S+Q314A+A364G;
[3115] V45L+A117S+L149R+V258P+A276S+A364G;
[3116] V45L+A117S+L149R+V258P+A276S+H358T+A364G+S388K;
[3117] V45L+L149R+N168G+V258P+A276S+H358T+A364G+S388K;
[3118] A25W+V45L+Q61K+L149R+V258P+A276S+A364G;
[3119] V45L+L149R+S214E+V258P+A276S+L281V+A364G;
[3120] V45N+L149R+V258P+A276S+A364G+S388K;
[3121] V45L+L149R+V258P+A276S+A286E+H358T+A364G;
[3122] D9E+V45L+L149R+V258P+A276S+A364G+S388K;
[3123] V45L+S92D+L149R+V258P+A276S+A364G+S388K;
[3124] V45L+A117S+L149R+T180Q+S214Q+V258P+A276S+A364G+S388K;
[3125] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388H;
[3126] V45L+A117S+L149R+S214Q+T215V+V258P+A276S+A364G+S388K;
[3127] V45L+A117S+L149R+S214Q+V258P+A276S+V350L+A364G+S388K;
[3128] A25W+V45L+L149R+S214E+T215I+V258P+A276S+A364G;
[3129] V45L+N127D+L149R+V258P+A276S+H358T+A364G+S388K;
[3130] A25W+V45L+L149R+V258P+A276S+A286E+A364G;
[3131] V45L+L149R+N168G+V258P+A276S+L281V+A364G;
[3132] V45L+Q61R+L149R+V258P+A276S+H358T+A364G;
[3133] V45L+L149R+G187S+V258P+A276S+A364G+S388K;
[3134] V45L+L149R+V258P+A276S+L281V+Q314A+A364G;
[3135] V45L+L149R+V258P+A276S+L281V+H358T+A364G;
[3136] V45L+L149R+A170S+V258P+A276S+H358T+A364G;
[3137] V45L+L149R+A170S+V258P+A276S+A364G+S388K;
[3138] V45L+L149R+T215V+V258P+A276S+A364G+S388K;
[3139] V45L+L149R+V258P+A276Q+L281V+A364G;
[3140] V45L+T70R+A117S+L149R+S214Q+C243S+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[3141] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V+C522V;
[3142] A25W+V45L+L149R+V258P+A276S+Q314A;
[3143] V45L+L149R+V258P+A276Q+H358T+A364G+S388K;
[3144] A25W+V45N+L149R+S214E+V258P+A276S+A364G;
[3145] V45L+L149R+V258P+A276S+A286E+A364G;
[3146] V45L+L149R+V258P+A276S+A286S+H358T+A364G;
[3147] A25W+V45L+L149R+G187S+V258P+A276S+A364G;
[3148] V45L+L149R+T180Q+V258P+A276S+L281V+A364G;
[3149] A25W+V45L+L149R+A276Q+L281V+A364G;
[3150] V45L+S92D+L149R+V258P+A276S+L281V+A364G;
[3151] V45L+Q61R+L149R+V258P+A276S+L281V+A364G;
[3152] V45L+L149R+A170S+V258P+A276S+L281V+A364G;
[3153] D11E+A25W+V45L+L149R+V258P+A276S+A364G;
[3154] A25W+V45L+Q61R+L149R+V258P+A276S+A364G;
[3155] A25W+V45L+L149R+T215V+V258P+A276S+A364G;
[3156] D9E+V45L+L149R+V258P+A276S+L281V+A364G;
[3157] A25W+V45L+L149R+V258P+A276S+V350L+A364G;
[3158] V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+A364G+S388K;
[3159] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+Y391V;
[3160] V45L+A117S+L149R+N168G+S214Q+V258P+A276S+A364G+S388K;
[3161] V45L+D113T+A117S+L149R+S214Q+V258P+A276S+A364G+S388K;
[3162] A25W+V45L+L149R+V258P+A276S+A286E;
[3163] A25W+V45L+L149R+V258P+A276S+L281V;
[3164] A25W+V45L+D113T+L149R+V258P+A276S;
[3165] V45L+L149R+H219V+V258P+A276S+L281V+A364G;
[3166] V45L+L149R+T180Q+V258P+A276S+H358T+A364G;
[3167] V45L+L149R+T215V+V258P+A276S+L281V+A364G;
[3168] A25W+V45L+L149R+V258P+A276S+S282N+A364G;
[3169] A25W+V45L+L149R+T215I+V258P+A276S+A364G;
[3170] A25W+V45L+L149R+H219I+V258P+A276S+A364G;
[3171] V45L+A117S+L149R+V258P+A276S+L281V+A364G;
[3172] D9E+A25W+V45L+L149R+V258P+A276S+A364G;
[3173] V45L+L149R+S214Y+V258P+A276S+A364G+S388K;
[3174] A25W+V45L+L149R+T180Q+V258P+A276S+A364G;
[3175] A25W+V45L+L149R+V258P+A276S+L281V+A364G;
[3176] V45L+N127D+L149R+V258P+A276S+L281V+A364G;
[3177] V45L+L149R+S173Y+V258P+A276S+H358T+A364G;
[3178] V45L+Q61R+L149R+V258P+A276S+A364G+S388K;
[3179] M28P+V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K;
[3180] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388A;
[3181] V45N+A117S+L149R+S214Q+V258P+A276S+A364G+S388K;
[3182] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+T477K;
[3183] A25W+V45L+L149R+T180Q+V258P+A276S;
[3184] A25W+V45L+L149R+V258P+A276S+A286S;
[3185] A25W+V45L+L149R+G187S+S214E+V258P+A276S+A364G;
[3186] V45L+L149R+V258P+A276S+L281V+A286E+A364G;
[3187] A25W+V45L+L149R+W250Y+V258P+A276S+A364G;
[3188] A25W+V45L+L149R+V258P+N260H+A276S+A364G;
[3189] V45L+L149R+V258P+A276S+L281V+V350L+A364G;
[3190] A25W+V45L+L149R+A170S+V258P+A276S+A364G;
[3191] V45L+L149R+V258P+A276S+L281V+A286S+A364G;
[3192] V45L+L149R+V258P+A276S+L281V+S282N+A364G;
[3193] D11E+V45L+L149R+V258P+A276S+L281V+A364G;
[3194] V45L+Q61K+L149R+V258P+A276S+L281V+A364G;
[3195] V45L+L149R+T215I+V258P+A276S+L281V+A364G;
[3196] A25W+V45L+S92D+L149R+V258P+A276S+A364G;
[3197] V45L+L149R+S214Y+V258P+A276S+L281V+A364G;
[3198] V45L+L149R+T211H+V258P+A276S+L281V+A364G;
[3199] A25W+V45L+L149R+G187L+V258P+A276S+A364G;
[3200] V45L+S92D+L149R+V258P+A276S+H358T+A364G;
[3201] V45L+L149R+G187L+A276Q+L281V+A364G;
[3202] V45L+L149R+A276Q+L281V+V350L+A364G;
[3203] V45L+L149R+A276Q+L281V+A364G+S388K;
[3204] V45L+A117S+L149R+S214Y+V258P+A276S+A364G+S388K;
[3205] A25W+V45L+S92D+L149R+V258P+A276S;
[3206] A25W+V45L+L149R+G187L+V258P+A276S;
[3207] A25W+V45L+L149R+W250Y+V258P+A276S;
[3208] V45L+D113T+L149R+V258P+A276S+A364G;
[3209] V45L+L149R+G187K+V258P+A276S+H358T+A364G;
[3210] V45L+L149R+N163H+V258P+A276S+L281V+A364G;
[3211] A25W+V45L+T70R+L149R+V258P+A276S+A364G;
[3212] V45L+L149R+S173Y+V258P+A276S+L281V+A364G;
[3213] V45L+L149R+G187L+V258P+A276S+L281V+A364G;
[3214] V45L+L149R+G187K+V258P+A276S+L281V+A364G;
[3215] V45L+L149R+W250Y+V258P+A276S+H358T+A364G;
[3216] V45L+L149R+T211H+V258P+A276S+A364G+S388K;
[3217] V45L+L149R+N163H+V258P+A276S+A364G+S388K;
[3218] V45L+T70R+L149R+A276Q+L281V+A364G;
[3219] V45L+S92D+L149R+A276Q+L281V+A364G;
[3220] V45L+D113T+L149R+A276Q+L281V+A364G;
[3221] V45L+L149R+A276Q+L281V+Q314A+A364G;
[3222] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+S389V;
[3223] A25W+V45L+Q61K+L149R+V258P+A276S;
[3224] D9E+A25W+V45L+L149R+V258P+A276S;
[3225] V45L+T70R+L149R+V258P+A276S+A364G;
[3226] V45L+L149R+V258P+A276S+A286S+A364G+S388K;
[3227] A25W+V45L+L149R+S214Y+V258P+A276S+A364G;
[3228] A25W+V45L+D113T+L149R+V258P+A276S+A364G;
[3229] V45L+T70R+L149R+V258P+A276S+L281V+A364G;
[3230] A25W+V45L+N127D+L149R+V258P+A276S+A364G;
[3231] V45L+T70R+L149R+V258P+A276S+H358T+A364G;
[3232] V45L+L149R+N163H+V258P+A276S+A364G;
[3233] V45L+L149R+T180Q+A276Q+L281V+A364G;
[3234] V45L+L149R+A276Q+L281V+A286S+A364G;
[3235] A25W+V45L+L149R+A170S+V258P+A276S;
[3236] A25W+V45L+T70R+L149R+V258P+A276S;
[3237] A25W+V45L+L149R+S214E+V258P+A276S+A286S+A364G;
[3238] V45L+L149R+V258P+A276S+A286S+H358T+A364G+S388K;
[3239] V45L+L149R+H219I+V258P+A276S+L281V+A364G;
[3240] A25W+V45L+A117S+L149R+V258P+A276S+A364G;
[3241] A25W+V45L+L149R+N168G+V258P+A276S+A364G;
[3242] V45L+L149R+N168G+A276Q+L281V+A364G;
[3243] V45L+L149R+S173Y+A276Q+L281V+A364G;
[3244] V45L+L149R+W250Y+A276Q+L281V+A364G;
[3245] V45L+A117S+L149R+S173Y+S214Q+V258P+A276S+A364G+S388K;
[3246] A25W+V45L+L149R+A276Q+A286E+A364G;
[3247] A25W+V45L+L149R+A276Q+A364G+S388K;
[3248] V45L+N127D+L149R+V258P+A276S+H358T+A364G;
[3249] A25W+V45L+L149R+V258P+A276S;
[3250] V45L+N127D+L149R+A276Q+L281V+A364G;
[3251] V45L+L149R+A276Q+L281V+A286E+A364G;
[3252] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+V500T;
[3253] A25W+V45L+A117S+L149R+V258P+A276S;
[3254] A25W+V45L+L149R+H219V+V258P+A276S+A364G;
[3255] V45L+L149R+S173Y+V258P+A276S+H358T+A364G+S388K;
[3256] D11E+V45L+L149R+V258P+A276S+H358T+A364G;
[3257] V45L+A79C+L149R+V258P+A276S+N355G+A364G+S388K;
[3258] A24K+V45L+L149R+V258P+A276S+A364G;
[3259] V45L+L149R+V258P+A276S+S282N+A364G;
[3260] V45L+A117S+L149R+A276Q+L281V+A364G;
[3261] V45L+L149R+N260H+A276Q+L281V+A364G;
[3262] V45L+A117S+L149R+T211H+S214Q+V258P+A276S+A364G+S388K;
[3263] A25W+V45L+L149R+N168G+V258P+A276S;
[3264] A25W+V45L+L149R+G187S+V258P+A276S;
[3265] A25W+V45L+L149R+V258P+A276S+V350L;
[3266] A25W+V45L+Q61R+L149R+V258P+A276S;
[3267] A25W+V45L+L149R+G187L+S214E+V258P+A276S+A364G;
[3268] V45L+L149R+G187S+V258P+A276S+L281V+A364G;
[3269] A25W+V45L+L149R+N163H+V258P+A276S+A364G;
[3270] A25W+V45L+L149R+G187K+V258P+A276S+A364G;
[3271] V45N+L149R+V258P+A276S+L281V+A364G;
[3272] V45L+L149R+A276Q+L281V+A364G;
[3273] V45L+L149R+V258P+N260H+A276S+H358T+A364G;
[3274] V45L+L149R+A276Q+S282N+A364G;
[3275] V45L+S92D+A117S+L149R+S214Q+V258P+A276S+A364G+S388K;
[3276] A25W+V45L+L149R+V258P+A276S+S282N;
[3277] A25W+V45L+L149R+S173Y+V258P+A276S;
[3278] A25W+V45L+L149R+A276Q+A286S+A364G;
[3279] V45L+D113T+L149R+V258P+A276S+L281V+A364G;
[3280] V45L+L149R+S214Q+V258P+A276S+L281V+A364G+S388K;
[3281] V45L+D113T+L149R+V258P+A276S+H358T+A364G;
[3282] A25W+V45L+L149R+T215V+V258P+A276S;
[3283] V45L+L149R+N168G+V258P+A276S+H358T+A364G;
[3284] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+A472L;
[3285] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+S473K;
[3286] A25W+V45L+L149R+T215I+V258P+A276S;
[3287] A25W+V45L+L149R+T211H+V258P+A276S;
[3288] A25W+V45L+L149R+V258P+A276Q;
[3289] V45L+L149R+S214Q+T215V+V258P+A276S+A364G+S388K;
[3290] V45L+L149R+N163H+V258P+A276S+H358T+A364G+S388K;
[3291] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+A499L;
[3292] V45L+L149R+V258P+A276S+V350L+A364G;
[3293] V45L+A79C+A117S+L149R+V258P+A276S+A364G+S388K;
[3294] A25W+V45L+D113T+L149R+A276Q+A364G;
[3295] A25W+V45N+L149R+V258P+A276S+A364G;
[3296] V45L+T70R+L149R+A276Q+A364G;
[3297] A25W+V45L+L149R+H219I+V258P+A276S;
[3298] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+V498I;
[3299] M28P+V45L+L149R+V258P+A276S+A364G;
[3300] A25W+V45L+T70R+L149R+A276Q+A364G;
[3301] A25W+V45L+L149R+A276Q+Q314A+A364G;
[3302] V45L+L149R+A170S+V258P+A276S+H358T+A364G+S388K;
[3303] A25W+V45L+L149R+S214Y+V258P+A276S;
[3304] V45L+L149R+S214Y+V258P+A276S+H358T+A364G;
[3305] V45L+L149R+A276Q+L281V+H358T+A364G;
[3306] A25W+V45L+L149R+H219V+V258P+A276S;
[3307] V45L+A117S+L149R+N163H+S214Q+V258P+A276S+A364G+S388K;
[3308] D11E+A25W+V45L+L149R+V258P+A276S;
[3309] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+N527H;
[3310] A25W+V45L+A117S+L149R+A276Q+A364G;
[3311] V45L+L149R+V258P+L281V+A364G;
[3312] A25W+V45L+L149R+G187L+A276Q+A364G;
[3313] V45N+L149R+V258P+A276S+H358T+A364G;
[3314] V45L+A117S+L149R+S214Q+V258P+A276S+N355G+H358D+A364G+S388K+D470T+R483V;
[3315] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388H+D470T+R483V;
[3316] A25W+V45L+L149R+A276Q+A364G;
[3317] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+V497E;
[3318] A25W+V45L+L149R+N163H+A276Q+A364G;
[3319] A25W+V45L+L149R+S173Y+A276Q+A364G;
[3320] A25W+V45L+L149R+A276Q+S282N+A364G;
[3321] A25W+V45L+L149R+A276Q+H358T+A364G;
[3322] A25W+V45L+L149R+T180Q+A276Q+A364G;
[3323] V45L+A117S+L149R+V258P+A276S+H358T+A364G;
[3324] V45L+L149R+A276Q+Q314A+A364G;
[3325] V45L+L149R+G187K+V258P+A364G;
[3326] V45L+L149R+A276Q+A286E+A364G;
[3327] A25W+V45L+N127D+L149R+A276Q+A364G;
[3328] A25W+V45L+L149R+A170S+A276Q+A364G;
[3329] A25W+V45L+N127D+L149R+V258P+A276S;
[3330] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+T477V;
[3331] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+G503L;
[3332] A25W+M28P+V45L+L149R+V258P+A276S+A364G;
[3333] V45L+L149R+A276Q+H358T+A364G;
[3334] A25W+V45L+L149R+N168G+A276Q+A364G;
[3335] A25W+V45L+L149R+N260H+A276Q+A364G;
[3336] V45L+A117S+L149R+G187L+S214Q+V258P+A276S+A364G+S388K;
[3337] V45L+A117S+L149R+N163H+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[3338] V45L+A117S+L149R+S214Q+T215K+V258P+A276S+A364G+S388K;
[3339] A25W+V45L+L149R+G187K+V258P+A276S;
[3340] A25W+M28P+V45L+L149R+V258P+A276S;
[3341] A25W+V45N+L149R+V258P+A276S;
[3342] V45L+A117S+L149R+S214Q+V258P+A276S+N355G+H358D+A364G+S388K+D470T;
[3343] V45L+N127D+L149R+A276Q+A364G;
[3344] V45L+L149R+W250Y+A276Q+A364G;
[3345] V45L+L149R+W250Y+V258P+A364G;
[3346] V45L+L149R+N163H+A276Q+L281V+A364G;
[3347] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+Q385C+S388K;
[3348] A25W+V45L+L149R+S214E+T215K+V258P+A276S+A364G;
[3349] M28P+V45L+L149R+V258P+A276S+L281V+A364G;
[3350] V45L+L149R+A276Q+A364G+S388K;
[3351] A25W+V45L+L149R+V258P+A364G;
[3352] M28P+V45L+L149R+V258P+A276S+H358T+A364G;
[3353] V45L+A117S+L149R+S214Q+V258P+A276S+N355G+H358D+A364G+S388K;
[3354] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V+C540V;
[3355] V45L+L149R+N168G+A276Q+A364G;
[3356] V45L+A117S+L149R+A276Q+A364G;
[3357] V45L+L149R+N163H+V258P+A276S+H358T+A364G;
[3358] V45L+L149R+T215K+V258P+A276S+H358T+A364G;
[3359] A24K+V45L+L149R+A276Q+A364G;
[3360] V45L+L149R+A276Q+A286S+A364G;
[3361] V45L+L149R+V258P+A364G;
[3362] V45L+L149R+H219I+V258P+A276S+A364G+S388K;
[3363] V45L+L149R+A170S+A276Q+A364G;
[3364] V45L+L149R+T180Q+A276Q+A364G;
[3365] V45L+L149R+A276Q+V350L+A364G;
[3366] V45L+L149R+V258P+S282N+A364G;
[3367] V45L+L149R+A276Q+A364G;
[3368] V45L+L149R+A276S+A364G;
[3369] V45L+L149R+T215K+V258P+A276S+A364G+S388K;
[3370] V45L+A117S+L149R+S214Q+V258P+A276S+N355G+A364G+S388K+D470T;
[3371] V45L+L149R+V258P+A276S;
[3372] A25W+V45L+L149R+A276S+A364G;
[3373] V45L+L149R+G187S+V258P+A364G;
[3374] V45L+S92D+L149R+V258P+A276S+H358T+A364G+S388K;
[3375] A25W+L149R+V258P+A276S+A364G;
[3376] V45L+L149R+G187L+A276Q+A364G;
[3377] A25W+V45L+V258P+A276S+A364G;
[3378] V45L+L149R+N260H+A276Q+A364G;
[3379] V45L+L149R+W250Y+V258R+A364G;
[3380] V45L+L149R+N163H+A276Q+A364G;
[3381] V45L+S92D+L149R+A276Q+A364G;
[3382] V45L+L149R+S173Y+A276Q+A364G;
[3383] V45L+S92D+L149R+V258P+A364G;
[3384] V45L+L149R+W250Y+V258P+A276S+L281V+A364G V45L+L149R+L281V+A364G; and wherein the variant has xylanse activity and wherein the variant has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%, but less than 100% sequence identity to SEQ ID NO: 1, and wherein the variants have increased thermostability measured as increased melting temperature measured by TSA of at least 5° C. compared to the xylanase of SEQ ID NO: 1.
[3385] In one aspect, the present invention relates to xylanase variants comprises at least one of the following substitutions or combinations of substitutions:
[3386] V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+A286E+H358D+A364G+Q384A+S388K+V393H+D470T+R483V;
[3387] V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q384A+S388K+G394Q+D470T+R483V;
[3388] V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q384A+S388K+G394A+D470T+R483V;
[3389] V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q384A+S388K+V393H+D470T+R483V;
[3390] V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q384A+S388K+V393H+D470T+R483V;
[3391] V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q384A+S388K+G394A+D470T+R483V;
[3392] V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q384A+S388K+V393H+D470T+R483V;
[3393] V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q384A+S388K+G394A+D470T+R483V;
[3394] V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+A286E+H358D+A364G+Q384A+S388K+V393H+D470T+R483V;
[3395] V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q384A+S388K+V393H+D470T+R483V;
[3396] V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q384A+S388K+G394A+D470T+R483V;
[3397] V45L+A79C+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[3398] V45L+A79C+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[3399] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[3400] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[3401] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[3402] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[3403] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[3404] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[3405] V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V+L530R;
[3406] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[3407] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[3408] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[3409] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[3410] V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+L530R;
[3411] V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V+L530R;
[3412] V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V+L530R;
[3413] V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+D470T+R483V+L530R;
[3414] V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V+L530R;
[3415] V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+D470T+R483V+L530R;
[3416] V45L+A117S+L149R+G187K+S214Q+V258P+A276S+A286E+H358D+A364G+Q384A+S388K+V393H+D470T+R483V;
[3417] V45L+A117S+L149R+G187K+S214Q+V258P+A276S+A286E+H358D+A364G+Q384A+S388K+N395D+D470T+R483V;
[3418] V45L+A117S+L149R+G187K+S214E+T215I+V258P+A276S+A286E+H358D+A364G+S388K+V393H+D470T+R483V;
[3419] V45L+A117S+L149R+G187K+S214E+T215I+V258P+A276S+A286E+H358D+A364G+S388K+N395D+D470T+R483V;
[3420] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+Q385C+S388K+D470T+R483V;
[3421] V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[3422] V45L+A79C+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V;
[3423] V45L+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+D470T+R483V;
[3424] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+T366I+S388K+D470T+R483V;
[3425] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[3426] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+Q384A+S388K+D470T+L530R;
[3427] V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[3428] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[3429] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+V393H+D470T+R483V;
[3430] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394A+D470T+R483V;
[3431] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+V393H+D470T+L530R;
[3432] V45L+A117S+L149R+S214Q+V258P+A276S+A286E+H358D+A364G+S388K+D470T+R483V;
[3433] D11E+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[3434] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+C468V+D470T+R483V;
[3435] V45L+A79C+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T V45L+A79C+L149R+S214E+V258P+A276S+A364G+S388K;
[3436] V45L+A117S+L149R+G187L+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[3437] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+Q384A+S388K+D470T+R483V;
[3438] V45L+A117S+L149R+G187K+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[3439] V45L+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+D470T+L530R;
[3440] V45L+A117S+L149R+S214E+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[3441] V45L+A117S+L149R+G187L+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[3442] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394Q+D470T+R483V;
[3443] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394A+D470T+L530R;
[3444] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+T366V+S388K+D470T+L530R;
[3445] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394Q+D470T+L530R;
[3446] V45L+A117S+L149R+S214Q+V258P+A276S+S282N+H358D+A364G+S388K+D470T+R483V;
[3447] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+N395D+D470T+R483V;
[3448] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N476D+R483V;
[3449] V45L+A117S+L149R+S214Q+V258P+A276S+V350L+H358D+A364G+S388K+D470T+R483V;
[3450] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T477K+R483V;
[3451] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+Q496R;
[3452] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+C468A+D470T+R483V;
[3453] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+W495E;
[3454] V45L+A117S+L149R+S214Q+V258P+A276S+A286E+H358D+A364G+S388K+D470T+L530R;
[3455] V45L+A117S+L149R+G187K+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[3456] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+Y391V+D470T+R483V;
[3457] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[3458] D9E+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[3459] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T477V+R483V;
[3460] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N476N+R483V;
[3461] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+V393R+D470T+R483V;
[3462] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T480L+L530R;
[3463] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S481A+L530R;
[3464] V45L+A117S+L149R+S214Q+W250Y+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[3465] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S481S+R483V;
[3466] V45L+A117S+L149R+S173Y+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[3467] V45L+T70R+A117S+L149R+S214Q+C243V+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[3468] V45L+A117S+L149R+T180Q+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[3469] D11E+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[3470] V45L+A117S+L149R+S214E+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[3471] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N476D+L530R;
[3472] V45L+A117S+L149R+S214Q+V258P+A276S+A286S+H358D+A364G+S388K+D470T+R483V;
[3473] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+Q496Q;
[3474] V45L+A117S+L149R+S214Q+V258P+A276Q+H358D+A364G+S388K+D470T+R483V;
[3475] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+Q496E;
[3476] V45L+Q61R+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[3477] V45L+A117S+L149R+S214Q+V258P+A276S+Q314A+H358D+A364G+S388K+D470T+L530R;
[3478] V45L+A117S+L149R+S214Q+V258P+A276Q+H358D+A364G+S388K+D470T+L530R;
[3479] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L478P+R483V;
[3480] A25W+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[3481] V45L+A117S+L149R+T180Q+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[3482] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+L484K;
[3483] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N474G+L530R;
[3484] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+N395D+D470T+L530R;
[3485] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+T366V+S388K+D470T+R483V;
[3486] V45L+A117S+L149R+N168G+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[3487] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+L484S;
[3488] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[3489] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+L484D;
[3490] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+S528H;
[3491] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+S501N;
[3492] V45L+A117S+L149R+S173Y+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[3493] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+A499L;
[3494] V45L+S92D+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[3495] V45L+A117S+L149R+S214Q+V258P+A276S+Q314A+H358D+A364G+S388K+D470T+R483V;
[3496] V45L+A79C+L149R+S214Q+V258P+A276S+A364G+S388K;
[3497] V45L+A117S+L149R+S214Q+V258P+A276S+N355G+H358D+A364G+S388K+D470T+L530R;
[3498] V45L+A117S+L149R+S214Q+V258P+A276S+V350L+H358D+A364G+S388K+D470T+L530R;
[3499] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S481S+L530R;
[3500] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+Q496E+L530R;
[3501] V45L+A117S+L149R+N168G+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[3502] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+V498I+L530R;
[3503] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470A+R483V;
[3504] V45N+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[3505] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+A499Y;
[3506] V45L+A79C+L149R+V258P+A276S+Q314A+A364G+S388K;
[3507] V45L+A79C+L149R+V258P+A276S+L281V+A364G+S388K;
[3508] V45L+A117S+L149R+S214Q+V258P+A276S+A286S+H358D+A364G+S388K+D470T+L530R;
[3509] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S501N+L530R;
[3510] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N476N+L530R;
[3511] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T477V+L530R;
[3512] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388H+D470T+L530R;
[3513] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L478N+L530R;
[3514] V45L+S92D+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[3515] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+V500V+L530R;
[3516] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+V500V;
[3517] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L478P+L530R;
[3518] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+S501E;
[3519] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+D525L+L530R;
[3520] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+G526T+L530R;
[3521] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N527H+L530R;
[3522] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T477K+L530R;
[3523] M28P+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[3524] D9E+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[3525] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S501E+L530R;
[3526] V45L+A117S+L149R+S214Q+W250Y+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[3527] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+A499L+L530R;
[3528] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+A472I+L530R;
[3529] V45L+A117S+N127D+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[3530] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+V500T+L530R;
[3531] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+N527H;
[3532] V45N+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[3533] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T480N+L530R;
[3534] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+V497P;
[3535] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+V498I;
[3536] V45L+A79C+L149R+S173Y+V258P+A276S+A364G+S388K;
[3537] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T480N+R483V;
[3538] V45L+A117S+L149R+S214Q+H219V+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[3539] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388A+D470T+L530R;
[3540] M28P+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[3541] V45L+A117S+L149R+A170S+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[3542] V45L+A79C+L149R+G187K+V258P+A276S+A364G+S388K;
[3543] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S389H+D470T+L530R;
[3544] V45L+D113T+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[3545] V45L+A117S+L149R+N163H+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[3546] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388A+D470T+R483V;
[3547] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388L+D470T+R483V;
[3548] V45L+Q61R+A79C+L149R+V258P+A276S+A364G+S388K;
[3549] V45L+A79C+L149R+N168G+V258P+A276S+A364G+S388K;
[3550] V45L+A117S+L149R+T211H+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[3551] V45L+A79C+L149R+T215V+V258P+A276S+A364G+S388K;
[3552] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+V500T;
[3553] V45L+A79C+L149R+V258P+A276S+A286S+A364G+S388K;
[3554] V45L+A79C+L149R+H219V+V258P+A276S+A364G+S388K;
[3555] V45L+A79C+L149R+A170S+V258P+A276S+A364G+S388K;
[3556] V45L+D113T+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[3557] V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[3558] V45L+D95N+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394A+D470T;
[3559] V45L+A79C+L149R+V258P+A276S+A364G+S388K;
[3560] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+G394A+D470T+R483V;
[3561] V45L+A93T+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+A499Y;
[3562] V45L+A117S+L149R+S214Q+T215I+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[3563] V45L+A117S+L149R+S214Q+H219I+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[3564] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L478N;
[3565] V45L+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+D470T;
[3566] V45L+A117S+L149R+S214E+V258P+A276S+H358D+A364G+S388K+D470T;
[3567] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+C468L+D470T+R483V;
[3568] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+Q385C+S388K+D470T+L530R;
[3569] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+T366I+S388K+D470T;
[3570] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S473G;
[3571] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L478P;
[3572] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394D+D470T;
[3573] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+Q384A+S388K+D470T+R483V;
[3574] D11E+V45L+A79C+L149R+V258P+A276S+A364G+S388K;
[3575] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+L530R;
[3576] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N529T;
[3577] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394Q+D470T;
[3578] V45L+A117S+L149R+G187L+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[3579] V45L+A79C+L149R+V258P+A276S+A286E+A364G+S388K;
[3580] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+G503L;
[3581] V45L+A117S+L149R+S214Q+V258P+A276S+Q314A+H358D+A364G+S388K+D470T;
[3582] V45L+A117S+L149R+S214Q+V258P+A276S+V350L+H358D+A364G+S388K+D470T;
[3583] V45L+A117S+L149R+G187K+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[3584] V45L+A117S+L149R+S214Q+W250Y+V258P+A276S+H358D+A364G+S388K+D470T;
[3585] V45L+A117S+L149R+S214Q+V258P+A276S+A286E+H358D+A364G+S388K+D470T;
[3586] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+Q384A+S388K+D470T;
[3587] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388R+D470T;
[3588] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S528H, V45L+A117S+L149R+S214Q+T215V+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[3589] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+Q496R;
[3590] V45L+A117S+L149R+N163H+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[3591] V45L+A117S+L149R+S214Q+V258P+A276S+S282N+H358D+A364G+S388K+D470T;
[3592] V45L+A117S+L149R+S214Q+V258P+A276Q+H358D+A364G+S388K+D470T;
[3593] D11E+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[3594] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+T366V+S388K+D470T;
[3595] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S473K;
[3596] V45L+A79C+L149R+T180Q+V258P+A276S+A364G+S388K;
[3597] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S481A+R483V;
[3598] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388R+D470T+R483V;
[3599] V45L+A117S+L149R+S214Q+V258P+A276S+Q314A+A364G+S388K+D470T+R483V;
[3600] V45L+S92D+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[3601] V45L+A117S+L149R+S214Q+V258P+N260H+A276S+H358D+A364G+S388K+D470T;
[3602] V45L+A117S+L149R+G187S+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[3603] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T477K;
[3604] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N474G;
[3605] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+N395D+S501N;
[3606] V45L+A117S+N127D+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[3607] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+V393R+D470T;
[3608] V45L+A117S+L149R+S173Y+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[3609] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388H+D470T;
[3610] V45L+A117S+L149R+S214Q+T215V+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[3611] V45L+A117S+L149R+G187S+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[3612] V45L+A117S+L149R+T211H+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[3613] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T480N;
[3614] V45L+A117S+L149R+N168G+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[3615] V45L+A79C+L149R+H219I+V258P+A276S+A364G+S388K;
[3616] V45L+L149R+S214E+V258P+A276S+H358D+A364G+D470T;
[3617] V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V;
[3618] V45L+D113T+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[3619] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+T366V+S388K+D470T+R483V;
[3620] V45L+A117S+L149R+S214Q+V258P+A276S+H358T+A364G+S388K+D470T+R483V;
[3621] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+V393R+D470T+R483V;
[3622] V45N+A79C+L149R+V258P+A276S+A364G+S388K;
[3623] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+Q496Q;
[3624] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+G394Q+D470T+R483V;
[3625] V45L+A79C+L149R+V258P+A276S+V350L+A364G+S388K;
[3626] V45L+L149R+S214E+V258P+A276S+H358D+A364G+D470T;
[3627] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+T366I+S388K+D470T+R483V;
[3628] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+G526T;
[3629] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L484S;
[3630] V45L+A79C+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K;
[3631] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+A499L;
[3632] V45L+A117S+L149R+S214Q+V258P+A276S+H358T+A364G+S388K+D470T+L530R;
[3633] V45L+A79C+D113T+L149R+V258P+A276S+A364G+S388K;
[3634] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+D525L;
[3635] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+V498I;
[3636] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388L+D470T;
[3637] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V;
[3638] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S528H+L530R;
[3639] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+N476D+R483V;
[3640] D9E+V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V;
[3641] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S501E;
[3642] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S481A;
[3643] V45L+A117S+L149R+S214Q+H219V+V258P+A276S+H358D+A364G+S388K+D470T;
[3644] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S481S;
[3645] V45L+A117S+L149R+G187K+S214Q+V258P+A276S+A364G+S388K+D470T+V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+N395D+D470T+R483V;
[3646] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+I469T+D470T+R483V;
[3647] V45L+A79C+N127D+L149R+V258P+A276S+A364G+S388K;
[3648] D9E+V45L+A79C+L149R+V258P+A276S+A364G+S388K;
[3649] V45L+L149R+S214E+V258P+A276S+H358D+A364G+D470T;
[3650] V45L+A117S+L149R+G187L+S214Q+V258P+A276S+A364G+S388K+D470T+R483V;
[3651] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N529T+L530R;
[3652] V45L+A79C+L149R+W250Y+V258P+A276S+A364G+S388K;
[3653] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+V497P;
[3654] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N527H;
[3655] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+Q496Q;
[3656] V45L+A117S+L149R+N168G+S214Q+V258P+A276S+A364G+S388K+D470T+R483V;
[3657] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+N476N+R483V;
[3658] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+T477V+R483V;
[3659] V45L+A117S+L149R+S214Q+V258P+A276S+V350L+A364G+S388K+D470T+R483V;
[3660] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+L478N+R483V;
[3661] V45L+A117S+L149R+S214E+V258P+A276S+A364G+S388K+D470T+R483V;
[3662] M28P+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[3663] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+V393H+D470T+R483V;
[3664] V45L+Q61R+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V;
[3665] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+V497P;
[3666] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+V498I;
[3667] V45L+A117S+L149R+S214Q+V258P+A276S+S282N+H358D+A364G+S388K+D470T+L530R;
[3668] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+C375V+S388K+G394A+D470T+R483V;
[3669] V45L+A117S+L149R+S214Q+V258P+A276S+A286E+A364G+S388K+D470T+R483V;
[3670] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388R+D470T+R483V;
[3671] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470A+R483V;
[3672] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+T477K+R483V;
[3673] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+Q496E;
[3674] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+Q496R;
[3675] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+A499L;
[3676] V45L+L149R+S214E+V258P+A276S+H358D+A364G+D470T;
[3677] V45L+L149R+S214E+V258P+A276S+H358D+A364G+D470T;
[3678] V45L+A117S+L149R+S214Q+T215I+V258P+A276S+H358D+A364G+S388K+D470T;
[3679] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+C468S+D470T+R483V;
[3680] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+Y391V+D470T+R483V;
[3681] V45L+A117S+L149R+S214Q+V258P+A276Q+A364G+S388K+D470T+R483V;
[3682] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+G503L+L530R;
[3683] V45L+A117S+L149R+S214Q+H219I+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[3684] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N476D;
[3685] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+V393H+D470T;
[3686] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V;
[3687] V45L+A117S+L149R+S214Q+V258P+A276S+A286S+A364G+S388K+D470T+R483V;
[3688] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+S501E;
[3689] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+N529T;
[3690] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+S501N;
[3691] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[3692] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+S481S+R483V;
[3693] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+L478P+R483V;
[3694] D11E+V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V;
[3695] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T477V;
[3696] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+V497P+L530R;
[3697] V45L+A117S+L149R+T211H+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[3698] V45L+A117S+L149R+S214Y+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[3699] V45L+A117S+L149R+S214Q+W250Y+V258P+A276S+A364G+S388K+D470T+R483V;
[3700] V45L+S92D+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V;
[3701] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+N527H;
[3702] V45N+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V;
[3703] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+Q385C+S388K+D470T;
[3704] V45L+A117S+L149R+S173Y+S214Q+V258P+A276S+A364G+S388K+D470T+R483V;
[3705] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388H+D470T+R483V;
[3706] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+S389H+D470T+V45L+A117S+L149R+S214Q+H219V+V258P+A276S+A364G+S388K+D470T+R483V;
[3707] V45L+A79C+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T;
[3708] V45L+A117S+L149R+S214Q+T215I+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[3709] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+Q496E;
[3710] V45L+A117S+L149R+A170S+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[3711] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S389V+D470T+R483V;
[3712] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S389V+D470T+L530R;
[3713] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388A+D470T;
[3714] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S389V+D470T;
[3715] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[3716] V45L+A117S+L149R+S214Q+H219I+V258P+A276S+A364G+S388K+D470T+R483V;
[3717] V45L+A79C+L149R+N163H+V258P+A276S+A364G+S388K;
[3718] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+A499Y;
[3719] V45L+A117S+L149R+S214Q+V258P+A276S+L281V+A364G+S388K+D470T+R483V;
[3720] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+V500T;
[3721] V45L+A117S+L149R+T180Q+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[3722] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+V500V;
[3723] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+G526T;
[3724] V45L+C60L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[3725] V45L+C69L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[3726] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388A+D470T+R483V;
[3727] V45L+A117S+L149R+S214Q+V258P+A276S+A286S+H358D+A364G+S388K+D470T;
[3728] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+V497D;
[3729] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470A+L530R;
[3730] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+D525L;
[3731] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N476N;
[3732] V45L+A117S+L149R+S214Q+V258P+A276S+L281V+A364G+S388K+D470T;
[3733] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+Q384A+S388K+D470T;
[3734] V45L+A117S+L149R+S214Q+V258P+A276S+A286E+A364G+S388K+D470T;
[3735] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+T477K;
[3736] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S389H+D470T;
[3737] V45L+A117S+L149R+S214Y+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[3738] V45L+A117S+L149R+S214Y+V258P+A276S+H358D+A364G+S388K+D470T;
[3739] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+G394A+D470T;
[3740] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+N476D;
[3741] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L478N+R483V;
[3742] V45L+C60A+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[3743] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+V393H+D470T;
[3744] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+N395D+D470T;
[3745] A25W+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[3746] V45L+T70R+A117S+L149R+S214Q+C243L+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[3747] V45L+A117S+L149R+S214Q+V258P+A276S+H358T+A364G+S388K+D470T;
[3748] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+L478N;
[3749] V45L+C60S+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[3750] V45L+A117S+L149R+S214Q+W250Y+V258P+A276S+A364G+S388K+D470T;
[3751] V45L+A117S+L149R+S214Q+T215V+V258P+A276S+A364G+S388K+D470T+R483V;
[3752] V45L+Q61R+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[3753] V45L+A117S+L149R+G187L+S214Q+V258P+A276S+A364G+S388K+D470T;
[3754] D9E+V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T;
[3755] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G;
[3756] V45L+C69A+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[3757] V45L+T70R+A117S+L149R+C161S+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[3758] V45L+A117S+L149R+S214Q+H219I+V258P+A276S+H358D+A364G+S388K+D470T;
[3759] V45L+A117S+L149R+S214Q+V258P+A276S+S282N+A364G+S388K+D470T;
[3760] V45L+A117S+L149R+T211H+S214Q+V258P+A276S+A364G+S388K+D470T+R483V;
[3761] V45L+D95N+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S473G;
[3762] V45L+T70R+D95N+A117S+L149R+S214Q+V258P+A276S+L356M+H358D+A364G+S388K;
[3763] D11E+V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T;
[3764] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+N476N;
[3765] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+G394D+D470T;
[3766] V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T;
[3767] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+G503L;
[3768] V45L+A117S+L149R+S214Q+V258P+A276S+A286S+A364G+S388K+D470T;
[3769] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470A;
[3770] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+G394Q+D470T;
[3771] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388R+D470T;
[3772] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+L478P;
[3773] V45L+A117S+L149R+S214Q+V258P+A276S+V350L+A364G+S388K+D470T;
[3774] V45L+D113T+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T;
[3775] V45L+A117S+L149R+T180Q+S214Q+V258P+A276S+A364G+S388K+D470T;
[3776] V45L+C69V+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[3777] V45L+A117S+L149R+S214Q+T215V+V258P+A276S+A364G+S388K+D470T+D525L;
[3778] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T;
[3779] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+V500T;
[3780] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+S389H+D470T;
[3781] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+V393R+D470T;
[3782] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+Q496R;
[3783] V45L+A117S+N127D+L149R+S214Q+V258P+A276S+A364G+S388K+D470T;
[3784] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+A499Y;
[3785] V45L+A117S+L149R+S214Q+T215V+V258P+A276S+H358D+A364G+S388K+D470T;
[3786] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T480L;
[3787] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388L+D470T;
[3788] V45L+A117S+L149R+S173Y+S214Q+V258P+A276S+A364G+S388K+D470T;
[3789] V45L+S92D+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T;
[3790] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+S389V+D470T+R483V;
[3791] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+N529T;
[3792] V45L+C60V+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[3793] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+V497E;
[3794] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+L478N;
[3795] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T;
[3796] M28P+V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T;
[3797] V45L+A117S+L149R+S214Q+V258P+A276Q+A364G+S388K+D470T;
[3798] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470V+R483V;
[3799] V45L+A117S+L149R+S214Y+V258P+A276S+A364G+S388K+D470T+R483V;
[3800] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+N395D;
[3801] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+T477K;
[3802] V45L+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K; and wherein the variant has xylanse activity and wherein the variant has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%, but less than 100% sequence identity to SEQ ID NO: 1, and wherein the variants have increased thermostability measured as increased melting temperature measured by TSA of at least 10° C. compared to the xylanase of SEQ ID NO: 1.
[3803] In one aspect, the present invention relates to xylanase variants comprises at least one of the following substitutions or combinations of substitutions:
[3804] V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+A286E+H358D+A3 64G+Q384A+S388K+V393H+D470T+R483V;
[3805] V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q3 84A+S388K+G394Q+D470T+R483V;
[3806] V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q3 84A+S388K+G394A+D470T+R483V;
[3807] V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q3 84A+S388K+V393H+D470T+R483V;
[3808] V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q3 84A+S388K+V393H+D470T+R483V;
[3809] V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q3 84A+S388K+G394A+D470T+R483V;
[3810] V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q3 84A+S388K+V393H+D470T+R483V;
[3811] V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q3 84A+S388K+G394A+D470T+R483V;
[3812] V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+A286E+H358D+A3 64G+Q384A+S388K+V393H+D470T+R483V;
[3813] V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q3 84A+S388K+V393H+D470T+R483V;
[3814] V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q3 84A+S388K+G394A+D470T+R483V;
[3815] V45L+A79C+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L 530R;
[3816] V45L+A79C+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R 483V;
[3817] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G 394A+D470T+R483V;
[3818] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G 394A+D470T+R483V;
[3819] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G 394A+D470T+R483V;
[3820] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G 394A+D470T+R483V;
[3821] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G 394A+D470T+R483V;
[3822] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G 394A+D470T+R483V;
[3823] V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G 394A+D470T+R483V+L530R;
[3824] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G 394A+D470T+R483V;
[3825] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G 394A+D470T+R483V;
[3826] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G 394A+D470T+R483V;
[3827] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G 394A+D470T+R483V;
[3828] V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G 394A+D470T+L530R;
[3829] V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G 394A+D470T+R483V+L530R;
[3830] V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G 394A+D470T+R483V+L530R;
[3831] V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+D 470T+R483V+L530R;
[3832] V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G 394A+D470T+R483V+L530R;
[3833] V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+D 470T+R483V+L530R;
[3834] V45L+A117S+L149R+G187K+S214Q+V258P+A276S+A286E+H358D+A364G+Q384A+S388K+V393H+D470T+R483V;
[3835] V45L+A117S+L149R+G187K+S214Q+V258P+A276S+A286E+H358D+A364G+Q384A+S388K+N395D+D470T+R483V; and wherein the variant has xylanse activity and wherein the variant has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%, but less than 100% sequence identity to SEQ ID NO: 1, and wherein the variants have increased thermostability measured as increased melting temperature measured by TSA of at least 15° C. compared to the xylanase of SEQ ID NO: 1.
[3836] In one aspect, the present invention relates to xylanase variants comprises at least one of the following substitutions or combinations of substitutions:
[3837] V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+A286E+H358D+A3 64G+Q384A+S388K+V393H+D470T+R483V;
[3838] V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q3 84A+S388K+G394Q+D470T+R483V;
[3839] V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q3 84A+S388K+G394A+D470T+R483V;
[3840] V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q3 84A+S388K+V393H+D470T+R483V;
[3841] V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q3 84A+S388K+V393H+D470T+R483V;
[3842] V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q3 84A+S388K+G394A+D470T+R483V;
[3843] V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q3 84A+S388K+V393H+D470T+R483V;
[3844] V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q3 84A+S388K+G394A+D470T+R483V;
[3845] V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+A286E+H358D+A3 64G+Q384A+S388K+V393H+D470T+R483V;
[3846] V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q3 84A+S388K+V393H+D470T+R483V;
[3847] V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q3 84A+S388K+G394A+D470T+R483V;
[3848] V45L+A79C+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L 530R;
[3849] V45L+A79C+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R 483V;
[3850] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G 394A+D470T+R483V;
[3851] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G 394A+D470T+R483V;
[3852] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G 394A+D470T+R483V;
[3853] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G 394A+D470T+R483V;
[3854] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G 394A+D470T+R483V;
[3855] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G 394A+D470T+R483V; and wherein the variant has xylanse activity and wherein the variant has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%, but less than 100% sequence identity to SEQ ID NO: 1, and wherein the variants have increased thermostability measured as increased melting temperature measured by TSA of at least 16° C. compared to the xylanase of SEQ ID NO: 1.
[3856] In one aspect, the present invention relates to xylanase variants comprises at least one of the following substitutions or combinations of substitutions:
[3857] V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+A286E+H358D+A3 64G+Q384A+S388K+V393H+D470T+R483V;
[3858] V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q3 84A+S388K+G394Q+D470T+R483V;
[3859] V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q3 84A+S388K+G394A+D470T+R483V;
[3860] V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q3 84A+S388K+V393H+D470T+R483V; and wherein the variant has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%, but less than 100% sequence identity to SEQ ID NO: 1, and wherein the variants have increased thermostability measured as increased melting temperature measured by TSA of at least 17° C. compared to the xylanase of SEQ ID NO: 1.
[3861] In one aspect, the present invention relates to xylanase variants comprises at least one of the following substitutions or combinations of substitutions:
[3862] V45L+A79C+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+V45L+A79C+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[3863] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[3864] V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[3865] V45L+D95N+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394A+D470T;
[3866] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+G394A+D470T+R483V;
[3867] V45L+A93T+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+A499Y;
[3868] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+Q384A+S388K+D470T+R483V;
[3869] V45L+A79C+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K;
[3870] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V;
[3871] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[3872] V45L+A79C+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T;
[3873] V45L+D95N+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S473G;
[3874] V45L+T70R+D95N+A117S+L149R+S214Q+V258P+A276S+L356M+H358D+A364G+S388K;
[3875] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470A;
[3876] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+L478N;
[3877] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+N395D;
[3878] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+T477K;
[3879] V45L+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K;
[3880] D11E+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K;
[3881] V45L+L149R+V258P+A276S+H358T+A364G;
[3882] A25W+V45L+L149R+V258P+A276S+A364G;
[3883] V45L+L149R+S214Q+V258P+A276S+A364G+S388K;
[3884] V45L+L149R+V258P+A276S+L281V+A364G;
[3885] V45L+N127D+L149R+V258P+A276S+A364G+S388K;
[3886] V45L+L149R+V258P+A276S+H358T+A364G+S388K;
[3887] V45L+L149R+V258P+A276S+A364G+S388K;
[3888] V45L+L149R+W250Y+V258P+A276S+A364G+S388K;
[3889] V45L+L149R+V258P+A276S+A286E+A364G+S388K;
[3890] V45L+L149R+V258P+A276S+S282N+A364G+S388K;
[3891] V45L+L149R+S214Q+V258P+A276S+H358T+A364G;
[3892] A25W+V45L+L149R+V258P+A276Q+A364G;
[3893] V45L+L149R+V258P+A276S+A364G;
[3894] A25W+V45L+L149R+W250Y+A276Q+A364G;
[3895] A25W+V45L+L149R+A276Q+L281V+A364G;
[3896] A25W+V45L+L149R+A276Q+A286E+A364G;
[3897] A25W+V45L+L149R+A276Q+A364G+S388K;
[3898] V45L+L149R+V258P+L281V+A364G;
[3899] A25W+V45L+L149R+A276Q+A364G;
[3900] V45L+L149R+V258P+A364G;
[3901] V45L+L149R+V258P+S282N+A364G;
[3902] V45L+L149R+A276Q+A364G;
[3903] V45L+L149R+A276S+A364G;
[3904] V45L+L149R;
[3905] V45L+L149R+A364G;
[3906] V45L+L149R+V258R+A364G;
[3907] V258P+A276Q;
[3908] V258P+A276S;
[3909] V45L+A276S;
[3910] V45L+A276Q;
[3911] L149R+W250Y;
[3912] V258P+S388K;
[3913] A276Q+S388K;
[3914] W250Y+A276Q;
[3915] A276S+S388K;
[3916] A276Q+L281V;
[3917] W250Y+A276S;
[3918] A276S+L281V;
[3919] G187S+A276Q;
[3920] V45L+L281V;
[3921] V45L;
[3922] L149R;
[3923] A79C;
[3924] V45N;
[3925] V45L+D11E;
[3926] L149R+S388K;
[3927] L149R+D11E;
[3928] A364G+D11E;
[3929] S388K+D11E; and wherein the variant has xylanse activity and wherein the variant has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%, but less than 100% sequence identity to SEQ ID NO: 1, and wherein the variants have increased thermostability measured as increased melting temperature measured by n-DSF of at least 0.5° C. compared to the xylanase of SEQ ID NO: 1.
[3930] In one aspect, the present invention relates to xylanase variants comprises at least one of the following substitutions or combinations of substitutions:
[3931] V45L+A79C+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V;
[3932] V45L+A79C+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[3933] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[3934] V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[3935] V45L+D95N+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394A+D470T;
[3936] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+G394A+D470T+R483V;
[3937] V45L+A93T+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+A499Y;
[3938] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+Q384A+S388K+D470T+R483V;
[3939] V45L+A79C+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K;
[3940] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V;
[3941] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[3942] V45L+A79C+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T;
[3943] V45L+D95N+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S473G;
[3944] V45L+T70R+D95N+A117S+L149R+S214Q+V258P+A276S+L356M+H358D+A364G+S388K;
[3945] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470A;
[3946] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+L478N;
[3947] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+N395D;
[3948] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+T477K;
[3949] V45L+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K;
[3950] D11E+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K;
[3951] V45L+L149R+V258P+A276S+H358T+A364G;
[3952] A25W+V45L+L149R+V258P+A276S+A364G;
[3953] V45L+L149R+S214Q+V258P+A276S+A364G+S388K;
[3954] V45L+L149R+V258P+A276S+L281V+A364G;
[3955] V45L+N127D+L149R+V258P+A276S+A364G+S388K;
[3956] V45L+L149R+V258P+A276S+H358T+A364G+S388K;
[3957] V45L+L149R+V258P+A276S+A364G+S388K;
[3958] V45L+L149R+W250Y+V258P+A276S+A364G+S388K;
[3959] V45L+L149R+V258P+A276S+A286E+A364G+S388K;
[3960] V45L+L149R+V258P+A276S+S282N+A364G+S388K;
[3961] V45L+L149R+S214Q+V258P+A276S+H358T+A364G;
[3962] A25W+V45L+L149R+V258P+A276Q+A364G;
[3963] V45L+L149R+V258P+A276S+A364G;
[3964] A25W+V45L+L149R+W250Y+A276Q+A364G;
[3965] A25W+V45L+L149R+A276Q+L281V+A364G;
[3966] A25W+V45L+L149R+A276Q+A286E+A364G;
[3967] A25W+V45L+L149R+A276Q+A364G+S388K;
[3968] V45L+L149R+V258P+L281V+A364G;
[3969] A25W+V45L+L149R+A276Q+A364G;
[3970] V45L+L149R+V258P+A364G;
[3971] V45L+L149R+V258P+S282N+A364G;
[3972] V45L+L149R+A276Q+A364G;
[3973] V45L+L149R+A276S+A364G;
[3974] V45L+L149R;
[3975] V45L+L149R+A364G;
[3976] V45L+L149R+V258R+A364G;
[3977] V258P+A276Q;
[3978] V258P+A276S;
[3979] V45L+A276S;
[3980] V45L+A276Q;
[3981] L149R+W250Y;
[3982] V258P+S388K;
[3983] A276Q+S388K;
[3984] W250Y+A276Q;
[3985] A276S+S388K;
[3986] A276Q+L281V;
[3987] W250Y+A276S;
[3988] A276S+L281V;
[3989] G187S+A276Q;
[3990] V45L+L281V;
[3991] L149R;
[3992] A79C;
[3993] V45N;
[3994] V45L+D11E;
[3995] L149R+S388K;
[3996] L149R+D11E;
[3997] S388K+D11E; and wherein the variant has xylanse activity and wherein the variant has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%, but less than 100% sequence identity to SEQ ID NO: 1, and wherein the variants have increased thermostability measured as increased melting temperature measured by n-DSF of at least 2.0° C. compared to the xylanase of SEQ ID NO: 1.
[3998] In one aspect, the present invention relates to xylanase variants comprises at least one of the following substitutions or combinations of substitutions:
[3999] V45L+A79C+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V;
[4000] V45L+A79C+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[4001] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[4002] V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[4003] V45L+D95N+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394A+D470T;
[4004] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+G394A+D470T+V45L+A93T+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+A499Y;
[4005] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+Q384A+S388K+D470T+R483V;
[4006] V45L+A79C+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K;
[4007] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V;
[4008] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[4009] V45L+A79C+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T;
[4010] V45L+D95N+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S473G;
[4011] V45L+T70R+D95N+A117S+L149R+S214Q+V258P+A276S+L356M+H358D+A364G+S388K;
[4012] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470A;
[4013] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+L478N;
[4014] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+N395D;
[4015] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+T477K;
[4016] V45L+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K;
[4017] D11E+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K;
[4018] V45L+L149R+V258P+A276S+H358T+A364G;
[4019] A25W+V45L+L149R+V258P+A276S+A364G;
[4020] V45L+L149R+S214Q+V258P+A276S+A364G+S388K;
[4021] V45L+L149R+V258P+A276S+L281V+A364G;
[4022] V45L+N127D+L149R+V258P+A276S+A364G+S388K;
[4023] V45L+L149R+V258P+A276S+H358T+A364G+S388K;
[4024] V45L+L149R+V258P+A276S+A364G+S388K;
[4025] V45L+L149R+W250Y+V258P+A276S+A364G+S388K;
[4026] V45L+L149R+V258P+A276S+A286E+A364G+S388K;
[4027] V45L+L149R+V258P+A276S+S282N+A364G+S388K;
[4028] V45L+L149R+S214Q+V258P+A276S+H358T+A364G;
[4029] A25W+V45L+L149R+V258P+A276Q+A364G;
[4030] V45L+L149R+V258P+A276S+A364G;
[4031] A25W+V45L+L149R+W250Y+A276Q+A364G;
[4032] A25W+V45L+L149R+A276Q+L281V+A364G;
[4033] A25W+V45L+L149R+A276Q+A286E+A364G;
[4034] A25W+V45L+L149R+A276Q+A364G+S388K;
[4035] V45L+L149R+V258P+L281V+A364G;
[4036] A25W+V45L+L149R+A276Q+A364G;
[4037] V45L+L149R+V258P+A364G;
[4038] V45L+L149R+V258P+S282N+A364G;
[4039] V45L+L149R+A276Q+A364G;
[4040] V45L+L149R+A276S+A364G;
[4041] V45L+L149R;
[4042] V45L+L149R+A364G;
[4043] V45L+L149R+V258R+A364G;
[4044] V258P+A276Q;
[4045] V258P+A276S;
[4046] V45L+A276S;
[4047] V45L+A276Q;
[4048] L149R+W250Y;
[4049] V258P+S388K;
[4050] A276Q+S388K;
[4051] W250Y+A276Q;
[4052] A276S+S388K;
[4053] A276Q+L281V;
[4054] W250Y+A276S;
[4055] A276S+L281V;
[4056] G187S+A276Q;
[4057] A79C;
[4058] V45L+D11E;
[4059] L149R+S388K;
[4060] L149R+D11E; and wherein the variant has xylanse activity and wherein the variant has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%, but less than 100% sequence identity to SEQ ID NO: 1, and wherein the variants have increased thermostability measured as increased melting temperature measured by n-DSF of at least 2.5° C. compared to the xylanase of SEQ ID NO: 1.
[4061] In one aspect, the present invention relates to xylanase variants comprises at least one of the following substitutions or combinations of substitutions:
[4062] V45L+A79C+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V;
[4063] V45L+A79C+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+R483V;
[4064] V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[4065] V45L+D95N+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394A+D470T;
[4066] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+G394A+D470T+R483V;
[4067] V45L+A93T+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+A499Y;
[4068] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+Q384A+S388K+D470T+R483V;
[4069] V45L+A79C+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K;
[4070] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V;
[4071] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[4072] V45L+A79C+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T;
[4073] V45L+D95N+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S473G;
[4074] V45L+T70R+D95N+A117S+L149R+S214Q+V258P+A276S+L356M+H358D+A364G+S388K;
[4075] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470A;
[4076] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+L478N;
[4077] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+N395D;
[4078] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+T477K;
[4079] V45L+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K;
[4080] D11E+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K;
[4081] V45L+L149R+V258P+A276S+H358T+A364G;
[4082] A25W+V45L+L149R+V258P+A276S+A364G;
[4083] V45L+L149R+S214Q+V258P+A276S+A364G+S388K;
[4084] V45L+L149R+V258P+A276S+L281V+A364G;
[4085] V45L+N127D+L149R+V258P+A276S+A364G+S388K;
[4086] V45L+L149R+V258P+A276S+H358T+A364G+S388K;
[4087] V45L+L149R+V258P+A276S+A364G+S388K;
[4088] V45L+L149R+W250Y+V258P+A276S+A364G+S388K;
[4089] V45L+L149R+V258P+A276S+A286E+A364G+S388K;
[4090] V45L+L149R+V258P+A276S+S282N+A364G+S388K;
[4091] V45L+L149R+S214Q+V258P+A276S+H358T+A364G;
[4092] A25W+V45L+L149R+V258P+A276Q+A364G;
[4093] V45L+L149R+V258P+A276S+A364G;
[4094] A25W+V45L+L149R+W250Y+A276Q+A364G;
[4095] A25W+V45L+L149R+A276Q+L281V+A364G;
[4096] A25W+V45L+L149R+A276Q+A286E+A364G;
[4097] A25W+V45L+L149R+A276Q+A364G+S388K;
[4098] V45L+L149R+V258P+L281V+A364G;
[4099] A25W+V45L+L149R+A276Q+A364G;
[4100] V45L+L149R+V258P+A364G;
[4101] V45L+L149R+V258P+S282N+A364G;
[4102] V45L+L149R+A276Q+A364G;
[4103] V45L+L149R+A276S+A364G;
[4104] V45L+L149R;
[4105] V45L+L149R+A364G;
[4106] V45L+L149R+V258R+A364G;
[4107] V258P+A276Q;
[4108] V258P+A276S;
[4109] V45L+A276S;
[4110] V45L+A276Q;
[4111] L149R+W250Y;
[4112] V258P+S388K;
[4113] A276Q+S388K;
[4114] W250Y+A276Q;
[4115] A276S+S388K;
[4116] A276Q+L281V;
[4117] W250Y+A276S;
[4118] A276S+L281V;
[4119] L149R+S388K; and wherein the variant has xylanse activity and wherein the variant has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%, but less than 100% sequence identity to SEQ ID NO: 1, and wherein the variants have increased thermostability measured as increased melting temperature measured by n-DSF of at least 3.0° C. compared to the xylanase of SEQ ID NO: 1.
[4120] In one aspect, the present invention relates to xylanase variants comprises at least one of the following substitutions or combinations of substitutions:
[4121] V45L+A79C+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V;
[4122] V45L+A79C+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[4123] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[4124] V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[4125] V45L+D95N+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394A+D470T;
[4126] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+G394A+D470T+R483V;
[4127] V45L+A93T+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+A499Y;
[4128] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+Q384A+S388K+D470T+R483V;
[4129] V45L+A79C+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K;
[4130] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V;
[4131] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[4132] V45L+A79C+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T;
[4133] V45L+D95N+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S473G;
[4134] V45L+T70R+D95N+A117S+L149R+S214Q+V258P+A276S+L356M+H358D+A364G+S388K;
[4135] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470A;
[4136] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+L478N;
[4137] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+N395D;
[4138] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+T477K;
[4139] V45L+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K;
[4140] D11E+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K;
[4141] V45L+L149R+V258P+A276S+H358T+A364G;
[4142] A25W+V45L+L149R+V258P+A276S+A364G;
[4143] V45L+L149R+S214Q+V258P+A276S+A364G+S388K;
[4144] V45L+L149R+V258P+A276S+L281V+A364G;
[4145] V45L+N127D+L149R+V258P+A276S+A364G+S388K;
[4146] V45L+L149R+V258P+A276S+H358T+A364G+S388K;
[4147] V45L+L149R+V258P+A276S+A364G+S388K;
[4148] V45L+L149R+W250Y+V258P+A276S+A364G+S388K;
[4149] V45L+L149R+V258P+A276S+A286E+A364G+S388K;
[4150] V45L+L149R+V258P+A276S+S282N+A364G+S388K;
[4151] V45L+L149R+S214Q+V258P+A276S+H358T+A364G;
[4152] A25W+V45L+L149R+V258P+A276Q+A364G;
[4153] V45L+L149R+V258P+A276S+A364G;
[4154] A25W+V45L+L149R+W250Y+A276Q+A364G;
[4155] A25W+V45L+L149R+A276Q+L281V+A364G;
[4156] A25W+V45L+L149R+A276Q+A286E+A364G;
[4157] A25W+V45L+L149R+A276Q+A364G+S388K;
[4158] V45L+L149R+V258P+L281V+A364G;
[4159] A25W+V45L+L149R+A276Q+A364G;
[4160] V45L+L149R+V258P+A364G;
[4161] V45L+L149R+V258P+S282N+A364G;
[4162] V45L+L149R+A276Q+A364G;
[4163] V45L+L149R+A276S+A364G;
[4164] V45L+L149R;
[4165] V45L+L149R+A364G;
[4166] V45L+L149R+V258R+A364G;
[4167] V258P+A276Q;
[4168] V258P+A276S;
[4169] V45L+A276S;
[4170] V45L+A276Q;
[4171] V258P+S388K;
[4172] A276Q+S388K;
[4173] W250Y+A276Q;
[4174] A276S+S388K;
[4175] A276Q+L281V;
[4176] L149R+S388K; and wherein the variant has xylanse activity and wherein the variant has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%, but less than 100% sequence identity to SEQ ID NO: 1, and wherein the variants have increased thermostability measured as increased melting temperature measured by n-DSF of at least 3.5° C. compared to the xylanase of SEQ ID NO: 1.
[4177] In one aspect, the present invention relates to xylanase variants comprises at least one of the following substitutions or combinations of substitutions:
[4178] V45L+A79C+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V;
[4179] V45L+A79C+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[4180] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[4181] V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[4182] V45L+D95N+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394A+D470T;
[4183] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+G394A+D470T+R483V;
[4184] V45L+A93T+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+A499Y;
[4185] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+Q384A+S388K+D470T+R483V;
[4186] V45L+A79C+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K;
[4187] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V;
[4188] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[4189] V45L+A79C+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T;
[4190] V45L+D95N+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S473G;
[4191] V45L+T70R+D95N+A117S+L149R+S214Q+V258P+A276S+L356M+H358D+A364G+S388K;
[4192] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470A;
[4193] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+L478N;
[4194] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+N395D;
[4195] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+T477K;
[4196] V45L+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K;
[4197] D11E+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K;
[4198] V45L+L149R+V258P+A276S+H358T+A364G;
[4199] A25W+V45L+L149R+V258P+A276S+A364G;
[4200] V45L+L149R+S214Q+V258P+A276S+A364G+S388K;
[4201] V45L+L149R+V258P+A276S+L281V+A364G;
[4202] V45L+N127D+L149R+V258P+A276S+A364G+S388K;
[4203] V45L+L149R+V258P+A276S+H358T+A364G+S388K;
[4204] V45L+L149R+V258P+A276S+A364G+S388K;
[4205] V45L+L149R+W250Y+V258P+A276S+A364G+S388K;
[4206] V45L+L149R+V258P+A276S+A286E+A364G+S388K;
[4207] V45L+L149R+V258P+A276S+S282N+A364G+S388K;
[4208] V45L+L149R+S214Q+V258P+A276S+H358T+A364G;
[4209] A25W+V45L+L149R+V258P+A276Q+A364G;
[4210] V45L+L149R+V258P+A276S+A364G;
[4211] A25W+V45L+L149R+W250Y+A276Q+A364G;
[4212] A25W+V45L+L149R+A276Q+L281V+A364G;
[4213] A25W+V45L+L149R+A276Q+A286E+A364G;
[4214] A25W+V45L+L149R+A276Q+A364G+S388K;
[4215] V45L+L149R+V258P+L281V+A364G;
[4216] A25W+V45L+L149R+A276Q+A364G;
[4217] V45L+L149R+V258P+A364G;
[4218] V45L+L149R+V258P+S282N+A364G;
[4219] V45L+L149R+A276Q+A364G;
[4220] V45L+L149R+A276S+A364G;
[4221] V45L+L149R;
[4222] V45L+L149R+A364G;
[4223] V45L+L149R+V258R+A364G;
[4224] V45L+A276Q;
[4225] V258P+A276Q;
[4226] V258P+A276S;
[4227] V45L+A276S; and wherein the variant has xylanse activity and wherein the variant has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%, but less than 100% sequence identity to SEQ ID NO: 1, and wherein the variants have increased thermostability measured as increased melting temperature measured by n-DSF of at least 4.0° C. compared to the xylanase of SEQ ID NO: 1.
[4228] In one aspect, the present invention relates to xylanase variants comprises at least one of the following substitutions or combinations of substitutions:
[4229] V45L+A79C+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+V45L+A79C+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[4230] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[4231] V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[4232] V45L+D95N+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394A+D470T;
[4233] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+G394A+D470T+R483V;
[4234] V45L+A93T+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+A499Y;
[4235] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+Q384A+S388K+D470T+R483V;
[4236] V45L+A79C+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K;
[4237] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V;
[4238] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[4239] V45L+A79C+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T;
[4240] V45L+D95N+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S473G;
[4241] V45L+T70R+D95N+A117S+L149R+S214Q+V258P+A276S+L356M+H358D+A364G+S388K;
[4242] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470A;
[4243] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+L478N;
[4244] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+N395D;
[4245] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+T477K;
[4246] V45L+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K;
[4247] D11E+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K;
[4248] V45L+L149R+V258P+A276S+H358T+A364G;
[4249] A25W+V45L+L149R+V258P+A276S+A364G;
[4250] V45L+L149R+S214Q+V258P+A276S+A364G+S388K;
[4251] V45L+L149R+V258P+A276S+L281V+A364G;
[4252] V45L+N127D+L149R+V258P+A276S+A364G+S388K;
[4253] V45L+L149R+V258P+A276S+H358T+A364G+S388K;
[4254] V45L+L149R+V258P+A276S+A364G+S388K;
[4255] V45L+L149R+W250Y+V258P+A276S+A364G+S388K;
[4256] V45L+L149R+V258P+A276S+A286E+A364G+S388K;
[4257] V45L+L149R+V258P+A276S+S282N+A364G+S388K;
[4258] V45L+L149R+S214Q+V258P+A276S+H358T+A364G;
[4259] A25W+V45L+L149R+V258P+A276Q+A364G;
[4260] V45L+L149R+V258P+A276S+A364G;
[4261] A25W+V45L+L149R+W250Y+A276Q+A364G;
[4262] A25W+V45L+L149R+A276Q+L281V+A364G;
[4263] A25W+V45L+L149R+A276Q+A286E+A364G;
[4264] A25W+V45L+L149R+A276Q+A364G+S388K;
[4265] V45L+L149R+V258P+L281V+A364G;
[4266] A25W+V45L+L149R+A276Q+A364G;
[4267] V45L+L149R+V258P+A364G;
[4268] V45L+L149R+V258P+S282N+A364G;
[4269] V45L+L149R+A276Q+A364G;
[4270] V45L+L149R+A276S+A364G;
[4271] V45L+L149R;
[4272] V45L+L149R+A364G;
[4273] V45L+L149R+V258R+A364G;
[4274] V45L+A276Q; and wherein the variant has xylanse activity and wherein the variant has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%, but less than 100% sequence identity to SEQ ID NO: 1, and wherein the variants have increased thermostability measured as increased melting temperature measured by n-DSF of at least 4.5° C. compared to the xylanase of SEQ ID NO: 1.
[4275] In one aspect, the present invention relates to xylanase variants comprises at least one of the following substitutions or combinations of substitutions:
[4276] V45L+A79C+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V;
[4277] V45L+A79C+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[4278] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[4279] V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[4280] V45L+D95N+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394A+D470T;
[4281] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+G394A+D470T+R483V;
[4282] V45L+A93T+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+A499Y;
[4283] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+Q384A+S388K+D470T+R483V;
[4284] V45L+A79C+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K;
[4285] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V;
[4286] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[4287] V45L+A79C+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T;
[4288] V45L+D95N+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S473G;
[4289] V45L+T70R+D95N+A117S+L149R+S214Q+V258P+A276S+L356M+H358D+A364G+S388K;
[4290] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470A;
[4291] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+L478N;
[4292] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+N395D;
[4293] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+T477K;
[4294] V45L+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K;
[4295] D11E+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K;
[4296] V45L+L149R+V258P+A276S+H358T+A364G;
[4297] A25W+V45L+L149R+V258P+A276S+A364G;
[4298] V45L+L149R+S214Q+V258P+A276S+A364G+S388K;
[4299] V45L+L149R+V258P+A276S+L281V+A364G;
[4300] V45L+N127D+L149R+V258P+A276S+A364G+S388K;
[4301] V45L+L149R+V258P+A276S+H358T+A364G+S388K;
[4302] V45L+L149R+V258P+A276S+A364G+S388K;
[4303] V45L+L149R+W250Y+V258P+A276S+A364G+S388K;
[4304] V45L+L149R+V258P+A276S+A286E+A364G+S388K;
[4305] V45L+L149R+V258P+A276S+S282N+A364G+S388K;
[4306] V45L+L149R+S214Q+V258P+A276S+H358T+A364G;
[4307] A25W+V45L+L149R+V258P+A276Q+A364G;
[4308] V45L+L149R+V258P+A276S+A364G;
[4309] A25W+V45L+L149R+W250Y+A276Q+A364G;
[4310] A25W+V45L+L149R+A276Q+L281V+A364G;
[4311] A25W+V45L+L149R+A276Q+A286E+A364G;
[4312] A25W+V45L+L149R+A276Q+A364G+S388K;
[4313] V45L+L149R+V258P+L281V+A364G;
[4314] A25W+V45L+L149R+A276Q+A364G;
[4315] V45L+L149R+V258P+A364G;
[4316] V45L+L149R+V258P+S282N+A364G;
[4317] V45L+L149R+A276Q+A364G;
[4318] V45L+L149R+A276S+A364G;
[4319] V45L+L149R+V258R+A364G; and wherein the variant has xylanse activity and wherein the variant has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%, but less than 100% sequence identity to SEQ ID NO: 1, and wherein the variants have increased thermostability measured as increased melting temperature measured by n-DSF of at least 5.0° C. compared to the xylanase of SEQ ID NO: 1.
[4320] In one aspect, the present invention relates to xylanase variants comprises at least one of the following substitutions or combinations of substitutions:
[4321] V45L+A79C+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V;
[4322] V45L+A79C+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[4323] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[4324] V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[4325] V45L+D95N+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394A+D470T;
[4326] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+G394A+D470T+R483V;
[4327] V45L+A93T+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+A499Y;
[4328] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+Q384A+S388K+D470T+R483V;
[4329] V45L+A79C+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K;
[4330] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V;
[4331] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[4332] V45L+A79C+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T;
[4333] V45L+D95N+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S473G;
[4334] V45L+T70R+D95N+A117S+L149R+S214Q+V258P+A276S+L356M+H358D+A364G+S388K;
[4335] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470A;
[4336] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+L478N;
[4337] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+N395D;
[4338] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+T477K;
[4339] V45L+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K;
[4340] D11E+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K;
[4341] V45L+L149R+S214Q+V258P+A276S+A364G+S388K;
[4342] V45L+L149R+V258P+A276S+H358T+A364G+S388K;
[4343] V45L+L149R+W250Y+V258P+A276S+A364G+S388K;
[4344] V45L+L149R+V258P+A276S+A286E+A364G+S388K;
[4345] V45L+L149R+V258P+A276S+S282N+A364G+S388K;
[4346] V45L+L149R+S214Q+V258P+A276S+H358T+A364G; and wherein the variant has xylanse activity and wherein the variant has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%, but less than 100% sequence identity to SEQ ID NO: 1, and wherein the variants have increased thermostability measured as increased melting temperature measured by n-DSF of at least 10.0° C. compared to the xylanase of SEQ ID NO: 1.
[4347] In one aspect, the present invention relates to xylanase variants comprises the following combinations of substitutions: V45L+A79C+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T and wherein the variant has xylanse activity and wherein the variant has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%, but less than 100% sequence identity to SEQ ID NO: 1, and wherein the variants have increased thermostability measured as increased melting temperature measured by n-DSF of at least 15.0° C. compared to the xylanase of SEQ ID NO: 1.
[4348] Parent Xylanase
[4349] The parent xylanase may be a polypeptide wherein said variant has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%, but less than 100% sequence identity with SEQ ID No: 1.
[4350] In one embodiment, the parent has a sequence identity to the polypeptide of SEQ ID NO: 1 of at least 60% e.g., at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%, or 100%, which have xylanase activity. In one embodiment, the amino acid sequence of the parent differs by no more than ten amino acids, e.g., by five amino acids, by four amino acids, by three amino acids, by two amino acids, and by one amino acid from the polypeptide of SEQ ID NO: 1.
[4351] The parent preferably comprises or consists of the amino acid sequence of SEQ ID NO: 1. In one embodiment the parent comprises or consists of the polypeptide of SEQ ID NO: 1. In another embodiment, the parent is an allelic variant of the polypeptide of SEQ ID NO: 1.
[4352] In another aspect, the parent is encoded by a polynucleotide that hybridizes under very low stringency conditions, low stringency conditions, medium stringency conditions, medium-high stringency conditions, high stringency conditions, or very high stringency conditions with (i) the mature polypeptide coding sequence, or (ii) the full-length complement of (i) or (ii) (Sambrook et al., 1989, Molecular Cloning, A Laboratory Manual, 2d edition, Cold Spring Harbor, N.Y.).
[4353] The polynucleotide or a subsequence thereof, as well as the polypeptide of SEQ ID NO: 1 or a fragment thereof, may be used to design nucleic acid probes to identify and clone DNA encoding a parent from strains of different genera or species according to methods well known in the art. In particular, such probes can be used for hybridization with the genomic DNA or cDNA of a cell of interest, following standard Southern blotting procedures, in order to identify and isolate the corresponding gene therein. Such probes can be considerably shorter than the entire sequence, but should be at least 15, e.g., at least 25, at least 35, or at least 70 nucleotides in length. Preferably, the nucleic acid probe is at least 100 nucleotides in length, e.g., at least 200 nucleotides, at least 300 nucleotides, at least 400 nucleotides, at least 500 nucleotides, at least 600 nucleotides, at least 700 nucleotides, at least 800 nucleotides, or at least 900 nucleotides in length. Both DNA and RNA probes can be used. The probes are typically labeled for detecting the corresponding gene (for example, with .sup.32P, .sup.3H, .sup.35S, biotin, or avidin). Such probes are encompassed by the present invention.
[4354] A genomic DNA or cDNA library prepared from such other strains may be screened for DNA that hybridizes with the probes described above and encodes a parent. Genomic or other DNA from such other strains may be separated by agarose or polyacrylamide gel electrophoresis, or other separation techniques. DNA from the libraries or the separated DNA may be transferred to and immobilized on nitrocellulose or other suitable carrier material. In order to identify a clone or DNA that hybridizes with parent or a subsequence thereof, the carrier material is used in a Southern blot.
[4355] The polypeptide may be a hybrid polypeptide in which a region of one polypeptide is fused at the N-terminus or the C-terminus of a region of another polypeptide.
[4356] The parent may be a fusion polypeptide or cleavable fusion polypeptide in which another polypeptide is fused at the N-terminus or the C-terminus of the polypeptide of the present invention. A fusion polypeptide is produced by fusing a polynucleotide encoding another polypeptide to a polynucleotide of the present invention. Techniques for producing fusion polypeptides are known in the art, and include ligating the coding sequences encoding the polypeptides so that they are in frame and that expression of the fusion polypeptide is under control of the same promoter(s) and terminator. Fusion polypeptides may also be constructed using intein technology in which fusion polypeptides are created post-translationally (Cooper et al., 1993, EMBO J. 12: 2575-2583; Dawson et al., 1994, Science 266: 776-779).
[4357] A fusion polypeptide can further comprise a cleavage site between the two polypeptides. Upon secretion of the fusion protein, the site is cleaved releasing the two polypeptides. Examples of cleavage sites include, but are not limited to, the sites disclosed in Martin et al., 2003, J. Ind. Microbiol. Biotechnol. 3: 568-576; Svetina et al., 2000, J. Biotechnol. 76: 245-251; Rasmussen-Wilson et al., 1997, Appl. Environ. Microbiol. 63: 3488-3493; Ward et al., 1995, Biotechnology 13: 498-503; and Contreras et al., 1991, Biotechnology 9: 378-381; Eaton et al., 1986, Biochemistry 25: 505-512; Collins-Racie et al., 1995, Biotechnology 13: 982-987; Carter et al., 1989, Proteins: Structure, Function, and Genetics 6: 240-248; and Stevens, 2003, Drug Discovery World 4: 35-48.
[4358] The parent may be obtained from microorganisms of any genus. For purposes of the present invention, the term “obtained from” as used herein in connection with a given source shall mean that the parent encoded by a polynucleotide is produced by the source or by a strain in which the polynucleotide from the source has been inserted. In one aspect, the parent is secreted extracellularly.
[4359] It will be understood that for the aforementioned species, the invention encompasses both the perfect and imperfect states, and other taxonomic equivalents, e.g., anamorphs, regardless of the species name by which they are known. Those skilled in the art will readily recognize the identity of appropriate equivalents.
[4360] Strains of these species are readily accessible to the public in a number of culture collections, such as the American Type Culture Collection (ATCC), Deutsche Sammlung von Mikroorganismen and Zellkulturen GmbH (DSMZ), Centraalbureau Voor Schimmelcultures (CBS), and Agricultural Research Service Patent Culture Collection, Northern Regional Research Center (NRRL).
[4361] The parent may be identified and obtained from other sources including microorganisms isolated from nature (e.g., soil, composts, water, etc.) or DNA samples obtained directly from natural materials (e.g., soil, composts, water, etc.) using the above-mentioned probes. Techniques for isolating microorganisms and DNA directly from natural habitats are well known in the art. A polynucleotide encoding a parent may then be obtained by similarly screening a genomic DNA or cDNA library of another microorganism or mixed DNA sample. Once a polynucleotide encoding a parent has been detected with the probe(s), the polynucleotide can be isolated or cloned by utilizing techniques that are known to those of ordinary skill in the art (see, e.g., Sambrook et al., 1989, supra).
[4362] Preparation of Variants
[4363] The xylanase variants can be prepared using any mutagenesis procedure known in the art, such as site-directed mutagenesis, synthetic gene construction, semi-synthetic gene construction, random mutagenesis, shuffling, etc.
[4364] Site-directed mutagenesis is a technique in which one or more (e.g., several) mutations are introduced at one or more defined sites in a polynucleotide encoding the parent.
[4365] Site-directed mutagenesis can be accomplished in vitro by PCR involving the use of oligonucleotide primers containing the desired mutation. Site-directed mutagenesis can also be performed in vitro by cassette mutagenesis involving the cleavage by a restriction enzyme at a site in the plasmid comprising a polynucleotide encoding the parent and subsequent ligation of an oligonucleotide containing the mutation in the polynucleotide. Usually the restriction enzyme that digests the plasmid and the oligonucleotide is the same, permitting sticky ends of the plasmid and the insert to ligate to one another. See, e.g., Scherer and Davis, 1979, Proc. Natl. Acad. Sci. USA 76: 4949-4955; and Barton et al., 1990, Nucleic Acids Res. 18: 7349-4966.
[4366] Site-directed mutagenesis can also be accomplished in vivo by methods known in the art. See, e.g., U.S. Patent Application Publication No. 2004/0171154; Storici et al., 2001, Nature Biotechnol. 19: 773-776; Kren et al., 1998, Nat. Med. 4: 285-290; and Calissano and Macino, 1996, Fungal Genet. Newslett. 43: 15-16.
[4367] Any site-directed mutagenesis procedure can be used in the present invention. There are many commercial kits available that can be used to prepare variants.
[4368] Synthetic gene construction entails in vitro synthesis of a designed polynucleotide molecule to encode a polypeptide of interest. Gene synthesis can be performed utilizing a number of techniques, such as the multiplex microchip-based technology described by Tian et al. (2004, Nature 432: 1050-1054) and similar technologies wherein oligonucleotides are synthesized and assembled upon photo-programmable microfluidic chips.
[4369] Single or multiple amino acid substitutions, deletions, and/or insertions can be made and tested using known methods of mutagenesis, recombination, and/or shuffling, followed by a relevant screening procedure, such as those disclosed by Reidhaar-Olson and Sauer, 1988, Science 241: 53-57; Bowie and Sauer, 1989, Proc. Natl. Acad. Sci. USA 86: 2152-2156; WO 95/17413; or WO 95/22625. Other methods that can be used include error-prone PCR, phage display (e.g., Lowman et al., 1991, Biochemistry 30: 10832-10837; U.S. Pat. No. 5,223,409; WO 92/06204) and region-directed mutagenesis (Derbyshire et al., 1986, Gene 46: 145; Ner et al., 1988, DNA 7: 127).
[4370] Mutagenesis/shuffling methods can be combined with high-throughput, automated screening methods to detect activity of cloned, mutagenized polypeptides expressed by host cells (Ness et al., 1999, Nature Biotechnology 17: 893-896). Mutagenized DNA molecules that encode active polypeptides can be recovered from the host cells and rapidly sequenced using standard methods in the art. These methods allow the rapid determination of the importance of individual amino acid residues in a polypeptide.
[4371] Semi-synthetic gene construction is accomplished by combining aspects of synthetic gene construction, and/or site-directed mutagenesis, and/or random mutagenesis, and/or shuffling. Semi-synthetic construction is typified by a process utilizing polynucleotide fragments that are synthesized, in combination with PCR techniques. Defined regions of genes may thus be synthesized de novo, while other regions may be amplified using site-specific mutagenic primers, while yet other regions may be subjected to error-prone PCR or non-error prone PCR amplification. Polynucleotide subsequences may then be shuffled.
[4372] Polynucleotides
[4373] The present invention also relates to isolated polynucleotides that encode any of the variants of the present invention. Accordingly, the present invention relates to isolated polynucleotides encoding a variant comprising a substitution at one or more positions corresponding to positions: 45, 149, 364, 258, 276, and 388 of SEQ ID NO: 1 and further comprises a substitution at one or more positions corresponding to positions: 9, 11, 18, 19, 20, 24, 25, 28, 40, 60, 61, 69, 70, 77, 79, 92, 93, 95, 113, 117, 127, 161, 163, 168, 170, 173, 180, 187, 190, 192, 211, 214, 215, 219, 234, 243, 250, 252, 260, 281, 282, 286, 314, 334, 340, 350, 355, 356, 358, 366, 375, 384, 385, 386, 389, 391, 393, 394, 395, 396, 446, 459, 468, 469, 470, 471, 472, 473, 474, 476, 477, 478, 480, 481, 483, 484, 495, 496, 497, 498, 499, 500, 501, 503, 522, 525, 526, 527, 528, 529, 530, and 540 of SEQ ID NO: 1, and wherein the variant has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%, but less than 100% sequence identity with the amino acid sequence set forth in SEQ ID NO: 1.
[4374] The techniques used to isolate or clone a polynucleotide are known in the art and include isolation from genomic DNA or cDNA, or a combination thereof. The cloning of the polynucleotides from genomic DNA can be effected, e.g., by using the polymerase chain reaction (PCR) or antibody screening of expression libraries to detect cloned DNA fragments with shared structural features. See, e.g., Innis et al., 1990, PCR: A Guide to Methods and Application, Academic Press, New York. Other nucleic acid amplification procedures such as ligase chain reaction (LCR), ligation activated transcription (LAT) and polynucleotide-based amplification (NASBA) may be used. The polynucleotides may be cloned from a strain of 2721i Trichoderma, Lecanicilfium, Simplicillium, Aspergillus, Cornyascus, Acrophialophora, Rhinocladiella, Nemania, Talaromyces, Collariella, Rigidoporous, and/or Loramyces, or a related organism and thus, for example, may be a species variant of the polypeptide encoding region of the polynucleotide.
[4375] Modification of a polynucleotide encoding xylanase variant(s) of the present invention may be necessary for synthesizing polypeptides substantially similar to the polypeptide. The term “substantially similar” to the polypeptide refers to non-naturally occurring forms of the polypeptide. These polypeptides may differ in some engineered way from the polypeptide isolated from its native source, e.g., variants that differ in specific activity, thermostability, pH optimum, or the like. The variants may be constructed on the basis of the polynucleotide presented as the mature polypeptide coding sequence e.g., a subsequence thereof, and/or by introduction of nucleotide substitutions that do not result in a change in the amino acid sequence of the polypeptide, but which correspond to the codon usage of the host organism intended for production of the enzyme, or by introduction of nucleotide substitutions that may give rise to a different amino acid sequence. For a general description of nucleotide substitution, see, e.g., Ford et al., 1991, Protein Expression and Purification 2: 95-107.
[4376] Nucleic Acid Constructs
[4377] The present invention also relates to nucleic acid constructs comprising a polynucleotide encoding a variant of the present invention operably linked to one or more (several) control sequences that direct the expression of the coding sequence in a suitable host cell under conditions compatible with the control sequences. Accordingly, the present invention relates to nucleic acid constructs comprising a polynucleotide encoding a variant comprising a substitution at one or more positions corresponding to positions: 45, 149, 364, 258, 276, and 388 of SEQ ID NO: 1 and further comprises a substitution at one or more positions corresponding to positions: 9, 11, 18, 19, 20, 24, 25, 28, 40, 60, 61, 69, 70, 77, 79, 92, 93, 95, 113, 117, 127, 161, 163, 168, 170, 173, 180, 187, 190, 192, 211, 214, 215, 219, 234, 243, 250, 252, 260, 281, 282, 286, 314, 334, 340, 350, 355, 356, 358, 366, 375, 384, 385, 386, 389, 391, 393, 394, 395, 396, 446, 459, 468, 469, 470, 471, 472, 473, 474, 476, 477, 478, 480, 481, 483, 484, 495, 496, 497, 498, 499, 500, 501, 503, 522, 525, 526, 527, 528, 529, 530, and 540 of SEQ ID NO: 1, and wherein the polynucleotide is operably linked to one or more control sequences that direct the expression of the coding sequence in a suitable host cell under conditions compatible with the control sequences. The polynucleotide may be manipulated in a variety of ways to provide for expression of the polypeptide. Manipulation of the polynucleotide prior to its insertion into a vector may be desirable or necessary depending on the expression vector. The techniques for modifying polynucleotides utilizing recombinant DNA methods are well known in the art.
[4378] The control sequence may be a promoter, a polynucleotide that is recognized by a host cell for expression of a polynucleotide encoding a polypeptide of the present invention. The promoter contains transcriptional control sequences that mediate the expression of the polypeptide. The promoter may be any polynucleotide that shows transcriptional activity in the host cell including mutant, truncated, and hybrid promoters, and may be obtained from genes encoding extracellular or intracellular polypeptides either homologous or heterologous to the host cell.
[4379] Examples of suitable promoters for directing transcription of the polynucleotide of the present invention in a bacterial host cell are the promoters obtained from the Bacillus amyloliquefaciens alpha-amylase gene (amyQ), Bacillus licheniformis alpha-amylase gene (amyL), Bacillus licheniformis penicillinase gene (penP), Bacillus stearothermophilus maltogenic amylase gene (amyM), Bacillus subtilis levansucrase gene (sacB), Bacillus subtilis xyIA and xyIB genes, Bacillus thuringiensis cryIIIA gene (Agaisse and Lereclus, 1994, Molecular Microbiology 13: 97-107), E. coli lac operon, E. coli trc promoter (Egon et al., 1988, Gene 69: 301-315), Streptomyces coelicolor agarase gene (dagA), and prokaryotic beta-lactamase gene (Villa-Kamaroff et al., 1978, Proc. Natl. Acad. Sci. USA 75: 3727-3731), as well as the tac promoter (DeBoer et al., 1983, Proc. Natl. Acad. Sci. USA 80: 21-25). Further promoters are described in “Useful proteins from recombinant bacteria” in Gilbert et al., 1980, Scientific American 242: 74-94; and in Sambrook et al., 1989, supra. Examples of tandem promoters are disclosed in WO 99/43835.
[4380] Examples of suitable promoters for directing transcription of the polynucleotide of the present invention in a filamentous fungal host cell are promoters obtained from the genes for Aspergillus nidulans acetamidase, Aspergillus niger neutral alpha-amylase, Aspergillus niger acid stable alpha-amylase, Aspergillus niger or Aspergillus awamori glucoamylase (glaA), Aspergillus oryzae TAKA amylase, Aspergillus oryzae alkaline protease, Aspergillus oryzae triose phosphate isomerase, Fusarium oxysporum trypsin-like protease (WO 96/00787), Fusarium venenatum amyloglucosidase (WO 00/56900), Fusarium venenatum Daria (WO 00/56900), Fusarium venenatum Quinn (WO 00/56900), Rhizomucor miehei lipase, Rhizomucor miehei aspartic proteinase, Trichoderma reesei beta-glucosidase, Trichoderma reesei cellobiohydrolase I, Trichoderma reesei cellobiohydrolase II, Trichoderma reesei endoglucanase I, Trichoderma reesei endoglucanase II, Trichoderma reesei endoglucanase III, Trichoderma reesei endoglucanase V, Trichoderma reesei xylanase I, Trichoderma reesei xylanase II, Trichoderma reesei xylanase III, Trichoderma reesei beta-xylosidase, and Trichoderma reesei translation elongation factor, as well as the NA2-tpi promoter (a modified promoter from an Aspergillus neutral alpha-amylase gene in which the untranslated leader has been replaced by an untranslated leader from an Aspergillus triose phosphate isomerase gene; non-limiting examples include modified promoters from an Aspergillus niger neutral alpha-amylase gene in which the untranslated leader has been replaced by an untranslated leader from an Aspergillus nidulans or Aspergillus oryzae triose phosphate isomerase gene); and mutant, truncated, and hybrid promoters thereof. Other promoters are described in U.S. Pat. No. 6,011,147.
[4381] In a yeast host, useful promoters are obtained from the genes for Saccharomyces cerevisiae enolase (ENO-1), Saccharomyces cerevisiae galactokinase (GAL1), Saccharomyces cerevisiae alcohol dehydrogenase/glyceraldehyde-3-phosphate dehydrogenase (ADH1, ADH2/GAP), Saccharomyces cerevisiae triose phosphate isomerase (TPI), Saccharomyces cerevisiae metallothionein (CUP1), and Saccharomyces cerevisiae 3-phosphoglycerate kinase. Other useful promoters for yeast host cells are described by Romanos et al., 1992, Yeast 8: 423-488.
[4382] The control sequence may also be a transcription terminator, which is recognized by a host cell to terminate transcription. The terminator is operably linked to the 3′-terminus of the polynucleotide encoding the polypeptide. Any terminator that is functional in the host cell may be used in the present invention.
[4383] Preferred terminators for bacterial host cells are obtained from the genes for Bacillus clausii alkaline protease (aprH), Bacillus licheniformis alpha-amylase (amyL), and Escherichia coli ribosomal RNA (rrnB).
[4384] Preferred terminators for filamentous fungal host cells are obtained from the genes for Aspergillus nidulans acetamidase, Aspergillus nidulans anthranilate synthase, Aspergillus niger glucoamylase, Aspergillus niger alpha-glucosidase, Aspergillus oryzae TAKA amylase, Fusarium oxysporum trypsin-like protease, Trichoderma reesei beta-glucosidase, Trichoderma reesei cellobiohydrolase I, Trichoderma reesei cellobiohydrolase II, Trichoderma reesei endoglucanase I, Trichoderma reesei endoglucanase II, Trichoderma reesei endoglucanase III, Trichoderma reesei endoglucanase V, Trichoderma reesei xylanase I, Trichoderma reesei xylanase II, Trichoderma reesei xylanase III, Trichoderma reesei beta-xylosidase, and Trichoderma reesei translation elongation factor.
[4385] Preferred terminators for yeast host cells are obtained from the genes for Saccharomyces cerevisiae enolase, Saccharomyces cerevisiae cytochrome C (CYC1), and Saccharomyces cerevisiae glyceraldehyde-3-phosphate dehydrogenase. Other useful terminators for yeast host cells are described by Romanos et al., 1992, supra.
[4386] The control sequence may also be an mRNA stabilizer region downstream of a promoter and upstream of the coding sequence of a gene which increases expression of the gene.
[4387] Examples of suitable mRNA stabilizer regions are obtained from a Bacillus thuringiensis cryIIIA gene (WO 94/25612) and a Bacillus subtilis SP82 gene (Hue et al., 1995, J. Bacteriol. 177: 3465-3471).
[4388] The control sequence may also be a leader, a nontranslated region of an mRNA that is important for translation by the host cell. The leader is operably linked to the 5′-terminus of the polynucleotide encoding the polypeptide. Any leader that is functional in the host cell may be used.
[4389] Preferred leaders for filamentous fungal host cells are obtained from the genes for Aspergillus oryzae TAKA amylase and Aspergillus nidulans triose phosphate isomerase.
[4390] Suitable leaders for yeast host cells are obtained from the genes for Saccharomyces cerevisiae enolase (ENO-1), Saccharomyces cerevisiae 3-phosphoglycerate kinase, Saccharomyces cerevisiae alpha-factor, and Saccharomyces cerevisiae alcohol dehydrogenase/glyceraldehyde-3-phosphate dehydrogenase (ADH2/GAP).
[4391] The control sequence may also be a polyadenylation sequence, a sequence operably linked to the 3′-terminus of the polynucleotide and, when transcribed, is recognized by the host cell as a signal to add polyadenosine residues to transcribed mRNA. Any polyadenylation sequence that is functional in the host cell may be used.
[4392] Preferred polyadenylation sequences for filamentous fungal host cells are obtained from the genes for Aspergillus nidulans anthranilate synthase, Aspergillus niger glucoamylase, Aspergillus niger alpha-glucosidase, Aspergillus oryzae TAKA amylase, and Fusarium oxysporum trypsin-like protease.
[4393] Useful polyadenylation sequences for yeast host cells are described by Guo and Sherman, 1995, Mol. Cellular Biol. 15: 5983-5990.
[4394] The control sequence may also be a signal peptide coding region that encodes a signal peptide linked to the N-terminus of a polypeptide and directs the polypeptide into the cell's secretory pathway. The 5′-end of the coding sequence of the polynucleotide may inherently contain a signal peptide coding sequence naturally linked in translation reading frame with the segment of the coding sequence that encodes the polypeptide. Alternatively, the 5′-end of the coding sequence may contain a signal peptide coding sequence that is heterologous to the coding sequence. A heterologous signal peptide coding sequence may be required where the coding sequence does not naturally contain a signal peptide coding sequence. Alternatively, a heterologous signal peptide coding sequence may simply replace the natural signal peptide coding sequence to enhance secretion of the polypeptide. However, any signal peptide coding sequence that directs the expressed polypeptide into the secretory pathway of a host cell may be used.
[4395] Effective signal peptide coding sequences for bacterial host cells are the signal peptide coding sequences obtained from the genes for Bacillus NCIB 11837 maltogenic amylase, Bacillus licheniformis subtilisin, Bacillus licheniformis beta-lactamase, Bacillus stearothermophilus alpha-amylase, Bacillus stearothermophilus neutral proteases (nprT, nprS, nprM), and Bacillus subtilis prsA. Further signal peptides are described by Simonen and Palva, 1993, Microbiol. Rev. 57: 109-137.
[4396] Effective signal peptide coding sequences for filamentous fungal host cells are the signal peptide coding sequences obtained from the genes for Aspergillus niger neutral amylase, Aspergillus niger glucoamylase, Aspergillus oryzae TAKA amylase, Humicola insolens cellulase, Humicola insolens endoglucanase V, Humicola lanuginosa lipase, and Rhizomucor miehei aspartic proteinase.
[4397] Useful signal peptides for yeast host cells are obtained from the genes for Saccharomyces cerevisiae alpha-factor and Saccharomyces cerevisiae invertase. Other useful signal peptide coding sequences are described by Romanos et al., 1992, supra.
[4398] The control sequence may also be a propeptide coding sequence that encodes a propeptide positioned at the N-terminus of a polypeptide. The resultant polypeptide is known as a proenzyme or propolypeptide (or a zymogen in some cases). A propolypeptide is generally inactive and can be converted to an active polypeptide by catalytic or autocatalytic cleavage of the propeptide from the propolypeptide. The propeptide coding sequence may be obtained from the genes for Bacillus subtilis alkaline protease (aprE), Bacillus subtilis neutral protease (nprT), Myceliophthora thermophila laccase (WO 95/33836), Rhizomucor miehei aspartic proteinase, and Saccharomyces cerevisiae alpha-factor.
[4399] Where both signal peptide and propeptide sequences are present, the propeptide sequence is positioned next to the N-terminus of a polypeptide and the signal peptide sequence is positioned next to the N-terminus of the propeptide sequence.
[4400] It may also be desirable to add regulatory sequences that regulate expression of the polypeptide relative to the growth of the host cell. Examples of regulatory sequences are those that cause expression of the gene to be turned on or off in response to a chemical or physical stimulus, including the presence of a regulatory compound. Regulatory sequences in prokaryotic systems include the lac, tac, and trp operator systems. In yeast, the ADH2 system or GAL1 system may be used. In filamentous fungi, the Aspergillus niger glucoamylase promoter, Aspergillus oryzae TAKA alpha-amylase promoter, and Aspergillus oryzae glucoamylase promoter, Trichoderma reesei cellobiohydrolase I promoter, and Trichoderma reesei cellobiohydrolase II promoter may be used. Other examples of regulatory sequences are those that allow for gene amplification. In eukaryotic systems, these regulatory sequences include the dihydrofolate reductase gene that is amplified in the presence of methotrexate, and the metallothionein genes that are amplified with heavy metals. In these cases, the polynucleotide encoding the polypeptide would be operably linked to the regulatory sequence.
Expression Vectors
[4401] The present invention also relates to recombinant expression vectors comprising a polynucleotide of the present invention, a promoter, and transcriptional and translational stop signals. Accordingly, the present invention relates to recombinant vectors comprising a polynucleotide encoding a variant comprising a substitution at one or more positions corresponding to positions: 45, 149, 364, 258, 276, and 388 of SEQ ID NO: 1 and further comprises a substitution at one or more positions corresponding to positions: 9, 11, 18, 19, 20, 24, 25, 28, 40, 60, 61, 69, 70, 77, 79, 92, 93, 95, 113, 117, 127, 161, 163, 168, 170, 173, 180, 187, 190, 192, 211, 214, 215, 219, 234, 243, 250, 252, 260, 281, 282, 286, 314, 334, 340, 350, 355, 356, 358, 366, 375, 384, 385, 386, 389, 391, 393, 394, 395, 396, 446, 459, 468, 469, 470, 471, 472, 473, 474, 476, 477, 478, 480, 481, 483, 484, 495, 496, 497, 498, 499, 500, 501, 503, 522, 525, 526, 527, 528, 529, 530, and 540 of SEQ ID NO: 1, a promoter, and transcriptional and translational stop signals. The various nucleotide and control sequences may be joined together to produce a recombinant expression vector that may include one or more (several) convenient restriction sites to allow for insertion or substitution of the polynucleotide encoding the variant at such sites. Alternatively, the polynucleotide may be expressed by inserting the polynucleotide or a nucleic acid construct comprising the polynucleotide into an appropriate vector for expression. In creating the expression vector, the coding sequence is located in the vector so that the coding sequence is operably linked with the appropriate control sequences for expression.
[4402] The recombinant expression vector may be any vector (e.g., a plasmid or virus) that can be conveniently subjected to recombinant DNA procedures and can bring about expression of the polynucleotide. The choice of the vector will typically depend on the compatibility of the vector with the host cell into which the vector is to be introduced. The vector may be a linear or closed circular plasmid.
[4403] The vector may be an autonomously replicating vector, i.e., a vector that exists as an extrachromosomal entity, the replication of which is independent of chromosomal replication, e.g., a plasmid, an extrachromosomal element, a minichromosome, or an artificial chromosome. The vector may contain any means for assuring self-replication. Alternatively, the vector may be one that, when introduced into the host cell, is integrated into the genome and replicated together with the chromosome(s) into which it has been integrated. Furthermore, a single vector or plasmid or two or more vectors or plasmids that together contain the total DNA to be introduced into the genome of the host cell, or a transposon, may be used.
[4404] The vector preferably contains one or more selectable markers that permit easy selection of transformed, transfected, transduced, or the like cells. A selectable marker is a gene the product of which provides for biocide or viral resistance, resistance to heavy metals, prototrophy to auxotrophs, and the like.
[4405] Examples of bacterial selectable markers are Bacillus licheniformis or Bacillus subtilis dal genes, or markers that confer antibiotic resistance such as ampicillin, chloramphenicol, kanamycin, neomycin, spectinomycin, or tetracycline resistance. Suitable markers for yeast host cells include, but are not limited to, ADE2, HIS3, LEU2, LYS2, MET3, TRP1, and URA3. Selectable markers for use in a filamentous fungal host cell include, but are not limited to, adeA (phosphoribosylaminoimidazole-succinocarboxamide synthase), adeB (phosphoribosyl-aminoimidazole synthase), amdS (acetamidase), argB (ornithine carbamoyltransferase), bar (phosphinothricin acetyltransferase), hph (hygromycin phosphotransferase), niaD (nitrate reductase), pyrG (orotidine-5′-phosphate decarboxylase), sC (sulfate adenyltransferase), and trpC (anthranilate synthase), as well as equivalents thereof. Preferred for use in an Aspergillus cell are Aspergillus nidulans or Aspergillus oryzae amdS and pyrG genes and a Streptomyces hygroscopicus bar gene. Preferred for use in a Trichoderma cell are adeA, adeB, amdS, hph, and pyrG genes.
[4406] The selectable marker may be a dual selectable marker system as described in WO 2010/039889. In one aspect, the dual selectable marker is a hph-tk dual selectable marker system.
[4407] The vector preferably contains an element(s) that permits integration of the vector into the host cell's genome or autonomous replication of the vector in the cell independent of the genome.
[4408] For integration into the host cell genome, the vector may rely on the polynucleotide's sequence encoding the polypeptide or any other element of the vector for integration into the genome by homologous or non-homologous recombination. Alternatively, the vector may contain additional polynucleotides for directing integration by homologous recombination into the genome of the host cell at a precise location(s) in the chromosome(s). To increase the likelihood of integration at a precise location, the integrational elements should contain a sufficient number of nucleic acids, such as 100 to 10,000 base pairs, 400 to 10,000 base pairs, and 800 to 10,000 base pairs, which have a high degree of sequence identity to the corresponding target sequence to enhance the probability of homologous recombination. The integrational elements may be any sequence that is homologous with the target sequence in the genome of the host cell. Furthermore, the integrational elements may be non-encoding or encoding polynucleotides. On the other hand, the vector may be integrated into the genome of the host cell by non-homologous recombination.
[4409] For autonomous replication, the vector may further comprise an origin of replication enabling the vector to replicate autonomously in the host cell in question. The origin of replication may be any plasmid replicator mediating autonomous replication that functions in a cell. The term “origin of replication” or “plasmid replicator” means a polynucleotide that enables a plasmid or vector to replicate in vivo.
[4410] Examples of bacterial origins of replication are the origins of replication of plasmids pBR322, pUC19, pACYC177, and pACYC184 permitting replication in E. coli, and pUB110, pE194, pTA1060, and pAM111 permitting replication in Bacillus.
[4411] Examples of origins of replication for use in a yeast host cell are the 2 micron origin of replication, ARS1, ARS4, the combination of ARS1 and CEN3, and the combination of ARS4 and CEN6.
[4412] Examples of origins of replication useful in a filamentous fungal cell are AMA1 and ANS1 (Gems et al., 1991, Gene 98: 61-67; Cullen et al., 1987, Nucleic Acids Res. 15: 9163-9175; WO 00/24883). Isolation of the AMA1 gene and construction of plasmids or vectors comprising the gene can be accomplished according to the methods disclosed in WO 00/24883.
[4413] More than one copy of a polynucleotide of the present invention may be inserted into a host cell to increase production of a polypeptide. An increase in the copy number of the polynucleotide can be obtained by integrating at least one additional copy of the sequence into the host cell genome or by including an amplifiable selectable marker gene with the polynucleotide where cells containing amplified copies of the selectable marker gene, and thereby additional copies of the polynucleotide, can be selected for by cultivating the cells in the presence of the appropriate selectable agent.
[4414] The procedures used to ligate the elements described above to construct the recombinant expression vectors of the present invention are well known to one skilled in the art (see, e.g., Sambrook et al., 1989, supra).
Host Cells
[4415] The present invention also relates to recombinant host cells, comprising a polynucleotide of the present invention operably linked to one or more (several) control sequences that direct the production of a variant of the present invention. Accordingly, the present invention relates to recombinant host cells, comprising a polynucleotide encoding a variant comprising a substitution at one or more positions corresponding to positions: 45, 149, 364, 258, 276, and 388 of SEQ ID NO: 1 and further comprises a substitution at one or more positions corresponding to positions: 9, 11, 18, 19, 20, 24, 25, 28, 40, 60, 61, 69, 70, 77, 79, 92, 93, 95, 113, 117, 127, 161, 163, 168, 170, 173, 180, 187, 190, 192, 211, 214, 215, 219, 234, 243, 250, 252, 260, 281, 282, 286, 314, 334, 340, 350, 355, 356, 358, 366, 375, 384, 385, 386, 389, 391, 393, 394, 395, 396, 446, 459, 468, 469, 470, 471, 472, 473, 474, 476, 477, 478, 480, 481, 483, 484, 495, 496, 497, 498, 499, 500, 501, 503, 522, 525, 526, 527, 528, 529, 530, and 540 of SEQ ID NO: 1, A construct or vector comprising a polynucleotide is introduced into a host cell so that the construct or vector is maintained as a chromosomal integrant or as a self-replicating extra-chromosomal vector as described earlier. The term “host cell” encompasses any progeny of a parent cell that is not identical to the parent cell due to mutations that occur during replication. The choice of a host cell will to a large extent depend upon the gene encoding the variant and its source.
[4416] The host cell may be any cell useful in the recombinant production of a variant, e.g., a prokaryote or a eukaryote.
[4417] In some embodiments, at least one of the one or more control sequences is heterologous to the polynucleotide encoding the xylanase variant(s).
[4418] In some embodiments, the recombinant host cell comprises at least two copies, e.g., three, four, or five, of the polynucleotide of the present invention.
[4419] The host cell may be any microbial or plant cell useful in the recombinant production of a polypeptide of the present invention, e.g., a prokaryotic cell or a fungal cell.
[4420] The host cell may be any microbial or plant cell useful in the recombinant production of a polypeptide of the present invention, e.g., a prokaryotic cell or a fungal cell.
[4421] The prokaryotic host cell may be any Gram-positive or Gram-negative bacterium. Gram-positive bacteria include, but are not limited to, Bacillus, Clostridium, Enterococcus, Geobacillus, Lactobacillus, Lactococcus, Oceanobacillus, Staphylococcus, Streptococcus, and Streptomyces. Gram-negative bacteria include, but are not limited to, Campylobacter, E. coli, Flavobacterium, Fusobacterium, Helicobacter, Ilyobacter, Neisseria, Pseudomonas, Salmonella, and Ureaplasma.
[4422] The bacterial host cell may be any Bacillus cell including, but not limited to, Bacillus alkalophilus, Bacillus amyloliquefaciens, Bacillus brevis, Bacillus circulans, Bacillus clausii, Bacillus coagulans, Bacillus firmus, Bacillus lautus, Bacillus lentus, Bacillus licheniformis, Bacillus megaterium, Bacillus pumilus, Bacillus stearothermophilus, Bacillus subtilis, and Bacillus thuringiensis cells.
[4423] The bacterial host cell may also be any Streptococcus cell including, but not limited to, Streptococcus equisimilis, Streptococcus pyogenes, Streptococcus uberis, and Streptococcus equi subsp. Zooepidemicus cells.
[4424] The bacterial host cell may also be any Streptomyces cell including, but not limited to, Streptomyces achromogenes, Streptomyces avermitilis, Streptomyces coelicolor, Streptomyces griseus, and Streptomyces lividans cells.
[4425] The introduction of DNA into a Bacillus cell may be effected by protoplast transformation (see, e.g., Chang and Cohen, 1979, Mol. Gen. Genet. 168: 111-115), competent cell transformation (see, e.g., Young and Spizizen, 1961, J. Bacteriol. 81: 823-829, or Dubnau and Davidoff-Abelson, 1971, J. Mol. Biol. 56: 209-221), electroporation (see, e.g., Shigekawa and Dower, 1988, Biotechniques 6: 742-751), or conjugation (see, e.g., Koehler and Thorne, 1987, J. Bacteriol. 169: 5271-5278). The introduction of DNA into an E. coli cell may be effected by protoplast transformation (see, e.g., Hanahan, 1983, J. Mol. Biol. 166: 557-580) or electroporation (see, e.g., Dower et al., 1988, Nucleic Acids Res. 16: 6127-6145). The introduction of DNA into a Streptomyces cell may be effected by protoplast transformation, electroporation (see, e.g., Gong et al., 2004, Folia Microbiol. (Praha) 49: 399-405), conjugation (see, e.g., Mazodier et al., 1989, J. Bacteriol. 171: 3583-3585), or transduction (see, e.g., Burke et al., 2001, Proc. Natl. Acad. Sci. USA 98: 6289-6294). The introduction of DNA into a Pseudomonas cell may be effected by electroporation (see, e.g., Choi et al., 2006, J. Microbiol. Methods 64: 391-397) or conjugation (see, e.g., Pinedo and Smets, 2005, Appl. Environ. Microbiol. 71: 51-57). The introduction of DNA into a Streptococcus cell may be effected by natural competence (see, e.g., Perry and Kuramitsu, 1981, Infect. Immun. 32: 1295-1297), protoplast transformation (see, e.g., Catt and Jollick, 1991, Microbios 68: 189-207), electroporation (see, e.g., Buckley et al., 1999, Appl. Environ. Microbiol. 65: 3800-3804), or conjugation (see, e.g., Clewell, 1981, Microbiol. Rev. 45: 409-436). However, any method known in the art for introducing DNA into a host cell can be used.
[4426] The host cell may be a fungal cell. “Fungi” as used herein includes the phyla Ascomycota, Basidiomycota, Chytridiomycota, and Zygomycota as well as the Oomycota and all mitosporic fungi (as defined by Hawksworth et al., In, Ainsworth and Bisby's Dictionary of The Fungi, 8th edition, 1995, CAB International, University Press, Cambridge, UK).
[4427] The fungal host cell may be a yeast cell. “Yeast” as used herein includes ascosporogenous yeast (Endomycetales), basidiosporogenous yeast, and yeast belonging to the Fungi Imperfecti (Blastomycetes). Since the classification of yeast may change in the future, for the purposes of this invention, yeast shall be defined as described in Biology and Activities of Yeast (Skinner, Passmore, and Davenport, editors, Soc. App. Bacteriol. Symposium Series No. 9, 1980).
[4428] The yeast host cell may be a Candida, Hansenula, Kluyveromyces, Pichia, Saccharomyces, Schizosaccharomyces, or Yarrowia cell, such as a Kluyveromyces lactis, Saccharomyces carlsbergensis, Saccharomyces cerevisiae, Saccharomyces diastaticus, Saccharomyces douglasii, Saccharomyces kluyveri, Saccharomyces norbensis, Saccharomyces oviformis, or Yarrowia lipolytica cell.
[4429] The fungal host cell may be a filamentous fungal cell. “Filamentous fungi” include all filamentous forms of the subdivision Eumycota and Oomycota (as defined by Hawksworth et al., 1995, supra). The filamentous fungi are generally characterized by a mycelial wall composed of chitin, cellulose, glucan, chitosan, mannan, and other complex polysaccharides. Vegetative growth is by hyphal elongation and carbon catabolism is obligately aerobic. In contrast, vegetative growth by yeasts such as Saccharomyces cerevisiae is by budding of a unicellular thallus and carbon catabolism may be fermentative.
[4430] The filamentous fungal host cell may be an Acremonium, Aspergillus, Aureobasidium, Bjerkandera, Ceriporiopsis, Chrysosporium, Coprinus, Coriolus, Cryptococcus, Filibasidium, Fusarium, Humicola, Magnaporthe, Mucor, Myceliophthora, Neocallimastix, Neurospora, Paecilomyces, Penicillium, Phanerochaete, Phlebia, Piromyces, Pleurotus, Schizophyllum, Talaromyces, Thermoascus, Thielavia, Tolypocladium, Trametes, or Trichoderma cell.
[4431] For example, the filamentous fungal host cell may be an Aspergillus awamori, Aspergillus foetidus, Aspergillus fumigatus, Aspergillus japonicus, Aspergillus nidulans, Aspergillus niger, Aspergillus oryzae, Bjerkandera adusta, Ceriporiopsis aneirina, Ceriporiopsis caregiea, Ceriporiopsis gilvescens, Ceriporiopsis pannocinta, Ceriporiopsis rivulosa, Ceriporiopsis subrufa, Ceriporiopsis subvermispora, Chrysosporium inops, Chrysosporium keratinophilum, Chrysosporium lucknowense, Chrysosporium merdarium, Chrysosporium pannicola, Chrysosporium queenslandicum, Chrysosporium tropicum, Chrysosporium zonatum, Coprinus cinereus, Coriolus hirsutus, Fusarium bactridioides, Fusarium cerealis, Fusarium crookwellense, Fusarium culmorum, Fusarium graminearum, Fusarium graminum, Fusarium heterosporum, Fusarium negundi, Fusarium oxysporum, Fusarium reticulatum, Fusarium roseum, Fusarium sambucinum, Fusarium sarcochroum, Fusarium sporotrichioides, Fusarium sulphureum, Fusarium torulosum, Fusarium trichothecioides, Fusarium venenatum, Humicola insolens, Humicola lanuginosa, Mucor miehei, Myceliophthora thermophila, Neurospora crassa, Penicillium purpurogenum, Phanerochaete chrysosporium, Phlebia radiata, Pleurotus eryngii, Talaromyces emersonii, Thielavia terrestris, Trametes villosa, Trametes versicolor, Trichoderma harzianum, Trichoderma koningii, Trichoderma longibrachiatum, Trichoderma reesei, or Trichoderma viride cell.
[4432] Fungal cells may be transformed by a process involving protoplast formation, transformation of the protoplasts, and regeneration of the cell wall in a manner known per se. Suitable procedures for transformation of Aspergillus and Trichoderma host cells are described in EP 238023, Yelton et al., 1984, Proc. Natl. Acad. Sci. USA 81: 1470-1474, and Christensen et al., 1988, Bio/Technology 6: 1419-1422. Suitable methods for transforming Fusarium species are described by Malardier et al., 1989, Gene 78: 147-156, and WO 96/00787. Yeast may be transformed using the procedures described by Becker and Guarente, In Abelson, J. N. and Simon, M. I., editors, Guide to Yeast Genetics and Molecular Biology, Methods in Enzymology, Volume 194, pp 182-187, Academic Press, Inc., New York; Ito et al., 1983, J. Bacteriol. 153: 163; and Hinnen et al., 1978, Proc. Natl. Acad. Sci. USA 75: 1920.
Methods of Production
[4433] The present invention also relates to methods of producing a variant, comprising: (a) cultivating a host cell of the present invention under conditions suitable for the expression of the variant; and (b) recovering the variant. Accordingly, the present invention relates to methods of producing a variant, comprising (a) cultivating a host cell comprising an expression vector or a polynucleotide encoding a variant comprising a substitution at one or more positions corresponding to positions: 45, 149, 364, 258, 276, and 388 of SEQ ID NO: 1 and further comprises a substitution at one or more positions corresponding to positions: 9, 11, 18, 19, 20, 24, 25, 28, 40, 60, 61, 69, 70, 77, 79, 92, 93, 95, 113, 117, 127, 161, 163, 168, 170, 173, 180, 187, 190, 192, 211, 214, 215, 219, 234, 243, 250, 252, 260, 281, 282, 286, 314, 334, 340, 350, 355, 356, 358, 366, 375, 384, 385, 386, 389, 391, 393, 394, 395, 396, 446, 459, 468, 469, 470, 471, 472, 473, 474, 476, 477, 478, 480, 481, 483, 484, 495, 496, 497, 498, 499, 500, 501, 503, 522, 525, 526, 527, 528, 529, 530, and 540 of SEQ ID NO: 1, under conditions suitable for the expression of the variant; and (b) recovering the variant.
[4434] In one aspect, the present invention relates to a method of obtaining a xylanase variant, comprising introducing into a parent xylanase a substitution at one or more positions corresponding to positions selected from the group consisting of 45, 149, 364, 258, 276, and 388 of SEQ ID NO: 1 and further comprises a substitution at one or more positions corresponding to positions: 9, 11, 18, 19, 20, 24, 25, 28, 40, 60, 61, 69, 70, 77, 79, 92, 93, 95, 113, 117, 127, 161, 163, 168, 170, 173, 180, 187, 190, 192, 211, 214, 215, 219, 234, 243, 250, 252, 260, 281, 282, 286, 314, 334, 340, 350, 355, 356, 358, 366, 375, 384, 385, 386, 389, 391, 393, 394, 395, 396, 446, 459, 468, 469, 470, 471, 472, 473, 474, 476, 477, 478, 480, 481, 483, 484, 495, 496, 497, 498, 499, 500, 501, 503, 522, 525, 526, 527, 528, 529, 530, and 540 of SEQ ID NO: 1, and the variant has xylanase activity; and recovering the variant.
[4435] The present invention also relates to methods of producing a variant of the present invention, comprising (a) cultivating a recombinant host cell of the present invention under conditions conducive for production of the variant; and optionally, (b) recovering the polypeptide.
[4436] The host cells are cultivated in a nutrient medium suitable for production of the polypeptide using methods known in the art. For example, the cells may be cultivated by shake flask cultivation, or small-scale or large-scale fermentation (including continuous, batch, fed-batch, or solid-state fermentations) in laboratory or industrial fermentors in a suitable medium and under conditions allowing the polypeptide to be expressed and/or isolated. The cultivation takes place in a suitable nutrient medium comprising carbon and nitrogen sources and inorganic salts, using procedures known in the art. Suitable media are available from commercial suppliers or may be prepared according to published compositions (e.g., in catalogues of the American Type Culture Collection). If the polypeptide is secreted into the nutrient medium, the polypeptide can be recovered directly from the medium. If the polypeptide is not secreted, it can be recovered from cell lysates. The variant may be detected using methods known in the art that are specific for the variants. These detection methods may include use of specific antibodies, formation of an enzyme product, or disappearance of an enzyme substrate. For example, an enzyme assay may be used to determine the activity of the variant.
[4437] The variant may be recovered by methods known in the art. For example, the variant may be recovered from the nutrient medium by conventional procedures including, but not limited to, collection, centrifugation, filtration, extraction, spray-drying, evaporation, or precipitation.
[4438] The variant may be purified by a variety of procedures known in the art including, but not limited to, chromatography (e.g., ion exchange, affinity, hydrophobic, chromatofocusing, and size exclusion), electrophoretic procedures (e.g., preparative isoelectric focusing), differential solubility (e.g., ammonium sulfate precipitation), SDS-PAGE, or extraction (see, e.g., Protein Purification, J.-C. Janson and Lars Ryden, editors, VCH Publishers, New York, 1989) to obtain substantially pure variants.
[4439] In an alternative aspect, the variant is not recovered, but rather a host cell of the present invention expressing a variant is used as a source of the variant.
Fermentation Broth Formulations or Cell Compositions
[4440] The present invention also relates to a fermentation broth formulation or a cell composition comprising a xylanase variant of the present invention. The fermentation broth product further comprises additional ingredients used in the fermentation process, such as, for example, cells (including, the host cells containing the gene encoding the polypeptide of the present invention which are used to produce the polypeptide of interest), cell debris, biomass, fermentation media and/or fermentation products. In some embodiments, the composition is a cell-killed whole broth containing organic acid(s), killed cells and/or cell debris, and culture medium.
[4441] The term “fermentation broth” as used herein refers to a preparation produced by cellular fermentation that undergoes no or minimal recovery and/or purification. For example, fermentation broths are produced when microbial cultures are grown to saturation, incubated under carbon-limiting conditions to allow protein synthesis (e.g., expression of enzymes by host cells) and secretion into cell culture medium. The fermentation broth can contain unfractionated or fractionated contents of the fermentation materials derived at the end of the fermentation. Typically, the fermentation broth is unfractionated and comprises the spent culture medium and cell debris present after the microbial cells (e.g., filamentous fungal cells) are removed, e.g., by centrifugation. In some embodiments, the fermentation broth contains spent cell culture medium, extracellular enzymes, and viable and/or nonviable microbial cells.
[4442] In an embodiment, the fermentation broth formulation and cell compositions comprise a first organic acid component comprising at least one 1-5 carbon organic acid and/or a salt thereof and a second organic acid component comprising at least one 6 or more carbon organic acid and/or a salt thereof. In a specific embodiment, the first organic acid component is acetic acid, formic acid, propionic acid, a salt thereof, or a mixture of two or more of the foregoing and the second organic acid component is benzoic acid, cyclohexanecarboxylic acid, 4-methylvaleric acid, phenylacetic acid, a salt thereof, or a mixture of two or more of the foregoing.
[4443] In one aspect, the composition contains an organic acid(s), and optionally further contains killed cells and/or cell debris. In one embodiment, the killed cells and/or cell debris are removed from a cell-killed whole broth to provide a composition that is free of these components.
[4444] The fermentation broth formulations or cell compositions may further comprise a preservative and/or anti-microbial (e.g., bacteriostatic) agent, including, but not limited to, sorbitol, sodium chloride, potassium sorbate, and others known in the art.
[4445] The cell-killed whole broth or composition may contain the unfractionated contents of the fermentation materials derived at the end of the fermentation. Typically, the cell-killed whole broth or composition contains the spent culture medium and cell debris present after the microbial cells (e.g., filamentous fungal cells) are grown to saturation, incubated under carbon-limiting conditions to allow protein synthesis. In some embodiments, the cell-killed whole broth or composition contains the spent cell culture medium, extracellular enzymes, and killed filamentous fungal cells. In some embodiments, the microbial cells present in the cell-killed whole broth or composition can be permeabilized and/or lysed using methods known in the art.
[4446] A whole broth or cell composition as described herein is typically a liquid, but may contain insoluble components, such as killed cells, cell debris, culture media components, and/or insoluble enzyme(s). In some embodiments, insoluble components may be removed to provide a clarified liquid composition.
[4447] The whole broth formulations and cell compositions of the present invention may be produced by a method described in WO 90/15861 or WO 2010/096673.
Enzyme Compositions
[4448] The present invention also relates to compositions comprising a xylanase variant of the present invention. Preferably, the compositions are enriched in the xylanase variant of the invention. The term “enriched” indicates that the xylanase activity of the composition has been increased, e.g., with an enrichment factor of at least 1.1, such as at least 1.2, at least 1.3, at least 1.4, at least 1.5, at least 2.0, at least 3.0, at least 4.0, at least 5.0, at least 10.
[4449] Alternatively, the compositions may comprise multiple enzymatic activities, such as one or more (e.g., several) enzymes selected from the group consisting of xylanse, cellobiohydrolase, cellulase, endoglucanase, and/or arabinofuranosidase.
[4450] The compositions may be prepared in accordance with methods known in the art and may be in the form of a liquid or a dry composition. The compositions may be stabilized in accordance with methods known in the art.
[4451] Uses
[4452] An aspect of the present invention relates to the use of xylanase variant(s) in a method to increase the starch yield and/or gluten yield from corn kernels in a wet milling process.
[4453] An aspect of the present invention relates to the use of a xylanase variant of the present invention for producing a fermentation product, such as ethanol, from a gelatinized starch-containing material, using a fermenting organism, such as yeast (e.g., a strain of Saccharomyces, such as Saccharomyces cerevisiae).
[4454] An aspect of the present invention relates to the use of a xylanase variant of the present invention for producing a fermentation product, such as ethanol, from an ungelatinized starch-containing material, using a fermenting organism, such as yeast (e.g., a strain of Saccharomyces, such as Saccharomyces cerevisiae).
[4455] Another aspect of the present invention relates to the use of a xylanase variant of the present invention for producing a fermentation product, such as ethanol, from a cellulosic-containing material, using a fermenting organism, such as yeast (e.g., a strain of Saccharomyces, such as Saccharomyces cerevisiae).
[4456] Another aspect of the present invention relates to the use of a xylanase variant of the present invention for liquefying a starch-containing material.
[4457] Another aspect of the present invention relates to the use of a xylanase variant of the present invention for saccharifying a starch-containing material.
[4458] Another aspect of the present invention relates to the use of a xylanase variant of the present invention for saccharifying a cellulosic-containing material.
Processes of the Invention
[4459] Processes for Producing Fermentation Products from Un-Gelatinized Starch-Containing Material.
[4460] The invention relates to processes for producing fermentation products from starch-containing material without gelatinization (i.e., without cooking) of the starch-containing material (often referred to as a “raw starch hydrolysis” process). The fermentation product, such as ethanol, can be produced without liquefying the aqueous slurry containing the starch-containing material and water. In one embodiment a process of the invention includes saccharifying (e.g., milled) starch-containing material, e.g., granular starch, below the initial gelatinization temperature, preferably in the presence of an alpha-amylase and carbohydrate-source generating enzyme(s) to produce sugars that can be fermented into the fermentation product by a suitable fermenting organism. In this embodiment the desired fermentation product, e.g., ethanol, is produced from un-gelatinized (i.e., uncooked), preferably milled, cereal grains, such as corn.
[4461] Processes for producing a fermentation product from starch-containing material may comprise simultaneously saccharifying and fermenting starch-containing material using a carbohydrate-source generating enzymes and a fermenting organism at a temperature below the initial gelatinization temperature of said starch-containing material in the presence of an alpha-amylase of the invention. Saccharification and fermentation may also be separate.
[4462] In an aspect, the invention relates to processes for producing fermentation products, preferably ethanol, from starch-containing material comprising the steps of:
[4463] i) saccharifying the starch-containing material using a carbohydrate-source generating enzyme at a temperature below the initial gelatination temperature; and
[4464] ii) fermenting using a fermenting organism;
[4465] wherein at least one or more xylanase variant(s) of the invention are present or added during saccharification, fermentation or simultaneous saccharification and fermentation.
[4466] In some embodiments, at least two, at least three, at least four, or at least five xylanase variant(s) of the invention are present and/or added during saccharification, fermentation or simultaneous saccharification and fermentation.
[4467] The xylanase variant(s) of the invention are present or added in the above described processes for producing fermentation products from starch-containing material may be added exogenously during saccharification, fermentation or simultaneous saccharification and fermentation as mono-components, as enzyme blends or compositions comprising the xylanase variant(s) of the invention, and/or via in-situ expression and secretion of the xylanase variant(s) of the invention by the fermenting organism, e.g., a recombinant host cell or fermenting organism described herein (e.g., yeast, such as from the genus Saccharomyces, preferably Saccharomyces cerevisiae).
[4468] Processes for Producing Fermentation Products from Gelatinized Starch-Containing Material.
[4469] In this aspect, the invention relates to processes for producing fermentation products, especially ethanol, from starch-containing material, which process includes a liquefaction step and sequentially or simultaneously performed saccharification and fermentation steps.
[4470] Consequently, the invention relates to processes for producing fermentation products from starch-containing material comprising the steps of:
[4471] i) liquefying the starch-containing material at a temperature above the initial gelatinization temperature using an alpha-amylase;
[4472] ii) saccharifying using a glucoamylase; and
[4473] iii) fermenting using a fermenting organism;
[4474] wherein at least one or more xylanase variant(s) of the invention are present or added during saccharification, fermentation or simultaneous saccharification and fermentation.
[4475] In some embodiments, at least two, at least three, at least four, or at least five xylanase variant(s) of the invention are present and/or added during saccharification, fermentation or simultaneous saccharification and fermentation.
[4476] The xylanase variant(s) of the invention are present or added in the above described processes for producing fermentation products from starch-containing material may be added exogenously during saccharification, fermentation or simultaneous saccharification and fermentation as mono-components, as enzyme blends or compositions comprising the xylanase variant(s) of the invention, and/or via in-situ expression and secretion of the xylanase variant(s) of the invention by the fermenting organism, e.g., a recombinant host cell or fermenting organism described herein (e.g., yeast, such as from the genus Saccharomyces, preferably Saccharomyces cerevisiae).
[4477] Processes for Producing Fermentation Products from Cellulosic-Containing Material
[4478] In this aspect, the invention relates to processes for producing fermentation products, especially ethanol, from cellulosic-containing material, which process may include a pretreatment step and sequentially or simultaneously performed saccharification and fermentation steps.
[4479] Consequently, the invention relates to processes for producing fermentation products from cellulosic-containing material comprising the steps of:
[4480] i) optionally pretreating a cellulosic-containing material;
[4481] ii) saccharifying a cellulosic-containing material and/or pretreated cellulosic-containing material using a carbohydrate-source generating enzyme; and
[4482] iii) fermenting using a fermenting organism;
[4483] wherein at least one or more xylanase variant(s) of the invention are present or added during saccharifying step ii) or fermenting step iii).
[4484] In some embodiments, at least two, at least three, at least four, or at least five xylanase variant(s) of the invention are present and/or added during saccharifying step ii) or fermenting step iii).
[4485] The xylanase variant(s) of the invention are present or added in the above described processes for producing fermentation products from cellulosic-containing material may be added exogenously during saccharification, fermentation or simultaneous saccharification and fermentation as mono-components, as enzyme blends or compositions comprising the xylanase variant(s), and/or via in-situ expression and secretion of the xylanase variant(s) by the fermenting organism, e.g., a recombinant host cell or fermenting organism described herein (e.g., yeast, such as from the genus Saccharomyces, preferably Saccharomyces cerevisiae).
[4486] Steps ii) and iii) are carried out either sequentially or simultaneously. In a preferred embodiment steps ii) and iii) are carried out simultaneously. The alpha-amylase, an optional thermostable protease, may be added before and/or during liquefaction step i).
[4487] A composition of the invention may suitably be used in a process of the invention. A recombinant host cell or fermenting organism of the invention may suitably be used in a process of the invention. However, the enzymes may also be added separately.
[4488] Whether the process of the invention includes or does not include a liquefaction step or pretreatment step, the essential feature of the invention is that at xylanase variant(s) of the invention are present or added during liquefaction, saccharification, fermentation or simultaneous saccharification and fermentation. In one embodiment, at least one xylanase variant of the present invention is present or added during liquefaction. In one embodiment, at least one xylanase variant of the present invention is present or added during fermentation or simultaneous saccharification and fermentation. As noted above, the xylanase variant(s) may be added exogenously as a standalone enzyme or an enzyme blend or composition comprising at least one, at least two, at least three, at least four, or at least five xylanase variant(s), or expressed and secreted in situ by a recombinant host cell or fermenting organism of the present invention comprising at least one, at least two, at least three, at least four, or at least five xylanase variant(s).
[4489] Examples of other enzymes that can be added in addition to one or more xylanase variant(s) of the present invention during saccharification/fermentation/SSF, or used as a component of an enzyme blend or composition of the invention include, without limitation, alpha-amylases, endoglucanase, cellobhiohydrolases, beta-glucosidases, glucoamylases, hemicellulases, cellulases. Particularly, saccharification and/or fermentation or simultaneous saccharification and fermentation, is performed in the presence of at least one cellulase/cellulolytic composition. More particularly the cellulases/cellulolytic composition are derived from a strain of Trichoderma, in particular Trichoderma reesei, or a strain of Humicola, in particular Humicola insolens, or a strain of Chrysosporium, in particular Chrysosporium lucknowense. The cellulases/cellulolytic composition should at least comprise a beta-glucosidase, a cellobiohydrolase and an endoglucanase.
[4490] The pH during liquefaction may be between 4-7. In an embodiment, the pH during liquefaction is from 4.5-5.0, such as between 4.5-4.8. In another embodiment liquefaction is carried out at a pH above 5.0-6.5, such as above 5.0-6.0, such as above 5.0-5.5, such as between 5.2-6.2, such as around 5.2, such as around 5.4, such as around 5.6, such as around 5.8.
[4491] According to the invention the temperature is above the initial gelatinization temperature. The term “initial gelatinization temperature” refers to the lowest temperature at which solubilization of starch, typically by heating, begins. The temperature can vary for different starches.
[4492] In an embodiment, the temperature during liquefaction step i) is in the range from 70-100° C., such as between 75-100° C., preferably between 80-100° C., such as between 85-95° C., such as around between 88 and 92° C.
[4493] The aqueous slurry may contain from 10-55 w/w-% dry solids (DS), preferably 25-45 w/w-% dry solids (DS), more preferably 30-40 w/w-% dry solids (DS) of starch-containing material.
[4494] Liquefaction step i) is according to the invention carried out for 0.5-5 hours, such as 1-3 hours, such as typically around 2 hours.
[4495] The aqueous slurry may in an embodiment be jet-cooked to further gelatinize the slurry before being subjected to liquefaction in step i). The jet-cooking may be carried out at a temperature between 110-145° C., preferably 120-140° C., such as 125-135° C., preferably around 130° C. for about 1-15 minutes, preferably for about 3-10 minutes, especially around about 5 minutes.
[4496] Saccharification and Fermentation
[4497] One or more carbohydrate-source generating enzymes, in particular glucoamylase, may be present and/or added during saccharification step ii) and/or fermentation step iii). The carbohydrate-source generating enzyme may preferably be a glucoamylase, but may also be an enzyme selected from the group consisting of: beta-amylase, maltogenic amylase and alpha-glucosidase. The carbohydrate-source generating enzyme added during saccharification step ii) and/or fermentation step iii) is typically different from the optional carbohydrate-source generating enzyme, in particular thermostable glucoamylase, optionally added during liquefaction step i). In a preferred embodiment the carbohydrate-source generating enzymes, in particular glucoamylase, is added together with a fungal alpha-amylase.
[4498] When doing sequential saccharification and fermentation, saccharification step ii) may be carried out at conditions well-known in the art. For instance, the saccharification step ii) may last up to from about 24 to about 72 hours. In an embodiment, pre-saccharification is done. Pre-saccharification is typically done for 40-90 minutes at a temperature between 30-65° C., typically about 60° C. Pre-saccharification is in an embodiment followed by saccharification during fermentation in simultaneous saccharification and fermentation (“SSF). Saccharification is typically carried out at temperatures from 20-75° C., preferably from 40-70° C., typically around 60° C., and at a pH between 4 and 5, normally at about pH 4.5.
[4499] Simultaneous saccharification and fermentation (“SSF”) is widely used in industrial scale fermentation product production processes, especially ethanol production processes. When doing SSF the saccharification step ii) and the fermentation step iii) are carried out simultaneously. There is no holding stage for the saccharification, meaning that a fermenting organism, such as yeast, and enzyme(s), may be added together. However, it is also contemplated to add the fermenting organism and enzyme(s) separately. SSF is according to the invention typically carried out at a temperature from 25° C. to 40° C., such as from 28° C. to 35° C., such as from 30° C. to 34° C., preferably around about 32° C. In an embodiment fermentation is ongoing for 6 to 120 hours, in particular 24 to 96 hours. In an embodiment the pH is between 3.5-5, in particular between 3.8 and 4.3.
[4500] Fermenting Organisms
[4501] The term “Fermenting organism” refers to any organism, including bacterial and fungal organisms, especially yeast, suitable for use in a fermentation process and capable of producing the desired fermentation product. Especially suitable fermenting organisms are able to ferment, i.e., convert, sugars, such as glucose or maltose, directly or indirectly into the desired fermentation product, such as ethanol. Examples of fermenting organisms include fungal organisms, such as yeast. Preferred yeast includes strains of Saccharomyces spp., in particular, Saccharomyces cerevisiae.
[4502] Suitable concentrations of the viable fermenting organism during fermentation, such as SSF, are well known in the art or can easily be determined by the skilled person in the art. In one embodiment the fermenting organism, such as ethanol fermenting yeast, (e.g., Saccharomyces cerevisiae) is added to the fermentation medium so that the viable fermenting organism, such as yeast, count per mL of fermentation medium is in the range from 10.sup.5 to 10.sup.12, preferably from 10.sup.7 to 10.sup.10, especially about 5×10.sup.7.
[4503] Examples of commercially available yeast includes, e.g., RED STAR™ and ETHANOL RED™ yeast (available from Fermentis/Lesaffre, USA), FALI (available from Fleischmann's Yeast, USA), SUPERSTART and THERMOSACC™ fresh yeast (available from Ethanol Technology, WI, USA), BIOFERM AFT and XR (available from NABC—North American Bioproducts Corporation, GA, USA), GERT STRAND (available from Gert Strand AB, Sweden), and FERMIOL (available from DSM Specialties). Other useful yeast strains are available from biological depositories such as the American Type Culture Collection (ATCC) or the Deutsche Sammlung von Mikroorganismen and Zellkulturen GmbH (DSMZ), such as, e.g., BY4741 (e.g., ATCC 201388); Y108-1 (ATCC PTA.10567) and NRRL YB-1952 (ARS Culture Collection). Still other S. cerevisiae strains suitable as host cells DBY746, [Alpha][Eta]22, 5150-2B, GPY55-15Ba, CEN.PK, USM21, TMB3500, TMB3400, VTT-A-63015, VTT-A-85068, VTT-c-79093 and their derivatives as well as Saccharomyces sp. 1400, 424A (LNH-ST), 259A (LNH-ST) and derivatives thereof.
[4504] The fermenting organisms may be a host cell that expresses a heterologous xylanase variant(s) of the invention (e.g., any xylanase variant(s) described herein). Any xylanase variant(s) contemplated for a process, method, enzyme blend, or composition described herein is also contemplated for expression by a fermenting organism or host cell.
[4505] In one embodiment is a recombinant host cell (e.g., yeast host cell, such as a strain of Saccharomyces, for example Saccharomyces cerevisiae) comprising a heterologous polynucleotide encoding xylanase variant(s) (e.g., xylanase) (e.g., any xylanase described herein).
[4506] In one embodiment, a recombinant yeast host cell comprising a heterologous polynucleotide encoding a xylanase variant(s), wherein the polynucleotide comprises, consists, or consists essentially of the nucleotide sequence, or is a polynucleotide comprising, consisting of, or consisting essentially of a nucleotide sequence having at least 70% identity, at least 71% identity, at least 72% identity, at least 73% identity, at least 74% identity, at least 75% identity, at least 76% identity, at least 77% identity, at least 78% identity, at least 79% identity, at least 80% identity, at least 81% identity, at least 82% identity, at least 83% identity, at least 84% identity, at least 85% identity, at least 86% identity, at least 87% identity, at least 88% identity, at least 89% identity, at least 90% identity, at least 91% identity, at least 92% identity, at least 93% identity, at least 94% identity, at least 95% identity, at least 96% identity, at least 97% identity, at least 98% identity, or at least 99% identity to the polypeptide of SEQ ID NO: 1, which has xylanase activity.
[4507] The fermenting organisms may be a host cell that expresses heterologous polynucleotides encoding enzymes other than the xylanase of the present invention, or that expresses such enzymes in addition to the xylanase of the present invention.
[4508] Starch-Containing Material
[4509] Any suitable starch-containing material containing may be used according to the present invention. The starting material is generally selected based on the desired fermentation product. Examples of starch-containing materials, suitable for use in a process of the invention, include whole grains, corn, wheat, barley, rye, milo, sago, cassava, tapioca, sorghum, rice, peas, beans, or sweet potatoes, or mixtures thereof or starches derived there from, or cereals. Contemplated are also waxy and non-waxy types of corn and barley. In a preferred embodiment, the starch-containing material in a process for producing a fermentation product, wherein the fermentation product is ethanol, is corn or wheat.
[4510] Fermentation Products
[4511] The term “fermentation product” means a product produced by a process including a fermentation step using a fermenting organism. A fermentation product can be any substance derived from the fermentation. The fermentation product can be, without limitation, an alcohol (e.g., arabinitol, n-butanol, isobutanol, ethanol, glycerol, methanol, ethylene glycol, 1,3-propanediol [propylene glycol], butanediol, glycerin, sorbitol, and xylitol); an (e.g., pentane, hexane, heptane, octane, nonane, decane, undecane, and dodecane), a cycloalkane (e.g., cyclopentane, cyclohexane, cycloheptane, and cyclooctane), an alkene (e.g., pentene, hexene, heptene, and octene); an amino acid (e.g., aspartic acid, glutamic acid, glycine, lysine, serine, and threonine); a gas (e.g., methane, hydrogen (H.sub.2), carbon dioxide (CO.sub.2), and carbon monoxide (CO)); isoprene; a ketone (e.g., acetone); an organic acid (e.g., acetic acid, acetonic acid, adipic acid, ascorbic acid, citric acid, 2,5-diketo-D-gluconic acid, formic acid, fumaric acid, glucaric acid, gluconic acid, glucuronic acid, glutaric acid, 3-hydroxypropionic acid, itaconic acid, lactic acid, malic acid, malonic acid, oxalic acid, oxaloacetic acid, propionic acid, succinic acid, and xylonic acid); and polyketide.
[4512] In one embodiment, the fermentation product is an alcohol. The term “alcohol” encompasses a substance that contains one or more hydroxyl moieties. The alcohol can be, but is not limited to, n-butanol, isobutanol, ethanol, methanol, arabinitol, butanediol, ethylene glycol, glycerin, glycerol, 1,3-propanediol, sorbitol, xylitol. See, for example, Gong et al., 1999, Ethanol production from renewable resources, in Advances in Biochemical Engineering/Biotechnology, Scheper, T., ed., Springer-Verlag Berlin Heidelberg, Germany, 65: 207-241; Silveira and Jonas, 2002, Appl. Microbiol. Biotechnol. 59: 400-408; Nigam and Singh, 1995, Process Biochemistry 30(2): 117-124; Ezeji et al., 2003, World Journal of Microbiology and Biotechnology 19(6): 595-603. In one embodiment, the fermentation product is ethanol.
[4513] Preferably processes of the invention are used for producing an alcohol, such as ethanol. The fermentation product, such as ethanol, obtained according to the invention, may be used as fuel, which is typically blended with gasoline. However, in the case of ethanol it may also be used as potable ethanol.
[4514] Recovery
[4515] The fermentation product, e.g., ethanol, can optionally be recovered from the fermentation medium using any method known in the art including, but not limited to, chromatography, electrophoretic procedures, differential solubility, distillation, or extraction. For example, alcohol is separated from the fermented cellulosic material or fermented starch-containing material and purified by conventional methods of distillation. As another example, the desired fermentation product may be extracted from the fermentation medium by micro or membrane filtration techniques. Ethanol with a purity of up to about 96 vol. % can be obtained, which can be used as, for example, fuel ethanol, drinking ethanol, i.e., potable neutral spirits, or industrial ethanol.
Wet Milling Process
[4516] Corn kernels are wet milled in order to open up the kernels and separate the kernels into its four main constituents: starch, germ, fiber and gluten.
[4517] The wet milling process can vary significantly from mill to mill, however conventional wet milling usually comprises the following steps:
[4518] 1. Steeping
[4519] 2. Grinding
[4520] 3. Separation into streams comprising:
[4521] i) germ; and ii) fiber, starch and gluten
[4522] 4. Fine grinding
[4523] 5. Fiber washing, pressing and drying
[4524] 6. Starch/gluten separation, and
[4525] 7. Starch washing.
Steeping, Grinding and Germ Separation
[4526] Corn kernels are softened by soaking in water for between about 30 minutes to about 48 hours, preferably 30 minutes to about 15 hours, such as about 1 hour to about 6 hours at a temperature of about 50° C., such as between about 45° C. to 60° C. During steeping, the kernels absorb water, increasing their moisture levels from 15 percent to 45 percent and more than doubling in size. The optional addition of e.g. 0.1 percent sulphur dioxide (SO.sub.2) and/or NaHSO.sub.3 to the water prevents excessive bacteria growth in the warm environment. As the corn swells and softens, the mild acidity of the steep water begins to loosen the gluten bonds within the corn and release the starch. After the corn kernels are steeped they are cracked open to release the germ usually by a course grinding step. The germ contains corn oil. The germ is separated from the heavier density mixture of starch, gluten and fiber essentially by “floating” the germ segment free of the other substances under closely controlled conditions. This method serves to eliminate any adverse effect of traces of corn oil in later processing steps. Subsequently the germ may be dried and oil extracted. After separating the germ, the ground kernel mass comprising fiber, starch and gluten (protein) is usually subjected to a fine grinding step.
Fiber Washing, Pressing and Drying
[4527] To get maximum starch and gluten recovery, while keeping any fiber in the final product to an absolute minimum, it is necessary to wash the free starch and gluten from the fiber during processing. Therefore, the finely ground kernel mass is subjected to a fiberwashing procedure. Thereby free starch and gluten is separated from fiber during screening (washing) and collected as mill starch. The remaining fiber is then pressed to decrease the water content.
[4528] To get maximum starch and gluten recovery, while keeping any fiber in the final product to an absolute minimum, it is necessary to wash the free starch and gluten from the fiber fraction during processing. The fiber is collected, slurried and screened, typically after soaking, grinding and separation of germs from the corn kernels, to reclaim any residual starch or gluten in the corn kernel mass. This process is herein referred to as the fiber washing procedure/step.
Starch Gluten Separation
[4529] The starch-gluten suspension from the fiber-washing step, called mill starch, is separated into starch and gluten. Gluten has a low density compared to starch. By passing mill starch through a centrifuge, the gluten is readily spun out.
Starch Washing
[4530] The starch slurry from the starch separation step contains some insoluble protein and much of solubles. They have to be removed before a top quality starch (high purity starch) can be made. The starch, with just one or two percent protein remaining, is diluted, washed 8 to 14 times, re-diluted and washed again in hydro-clones to remove the last trace of protein and produce high quality starch, typically more than 99.5% pure.
[4531] Products of wet milling: Wet milling can be used to produce, without limitation, corn steep liquor, corn gluten feed, germ, corn oil, corn gluten meal, corn starch, modified corn starch, syrups such as corn syrup, and corn ethanol.
[4532] An aspect of the present invnetion is to provide a method to increase the total starch yield and/or gluten yield that can be obtained from corn kernels in a wet milling process, the method comprising: contacting corn kernels or a fraction of the corn kernels, particularly a fiber rich fraction, with an effective amount of a xylanase variant of the invention and optionally one or more hydrolytic enzymes.
[4533] In another specific embodiment the present invention provides a method to increase the total starch yield and/or gluten yield that can be obtained from corn kernels in a wet milling process, the method comprising the steps of:
[4534] a) soaking the corn kernels in water to produce soaked kernels;
[4535] b) grinding the soaked kernels to produce ground kernels;
[4536] c) separating germ from the ground kernels to produce a corn kernel mass comprising fiber, starch and gluten; and
[4537] d) subjecting the corn kernel mass to a fiber washing procedure separating starch and gluten from the fiber;
[4538] wherein at least a xylanase variant of the invention is present/added before or during step d).
[4539] The method may further comprise the steps of:
[4540] e) separating the starch from the gluten; and optionally
[4541] f) washing the starch.
[4542] Optionally the corn kernel mass comprising fiber, starch and gluten from step c) is subjected to a further grinding step, preferably a fine grinding step before the fiber washing procedure in step d).
[4543] In one embodiment, said corn kernels or a fiber rich fraction of said corn kernels is admixed with optionally with said one or more hydrolytic enzymes, before, or preferably during the step of subjecting the corn kernel mass to a fiber washing procedure.
[4544] In one embodiment, hydrolytic enzymes suitable for use in the method of the invention comprise one or more enzymes selected form the group consisting of: cellulases (EC 3.2.1.4), xylanases (EC 3.2.1.8), arabinofuranosidases (EC 3.2.1.55 (Non-reducing end alpha-L-arabinofuranosidases); EC 3.2.1.185 (Non-reducing end beta-L-arabinofuranosidases), cellobiohydrolase I (EC 3.2.1.150), cellobiohydrolase II (E.C. 3.2.1.91), cellobiosidase (E.C. 3.2.1.176), beta-glucosidase (E.C. 3.2.1.21), beta-xylosidases (EC 3.2.1.37), and proteases (E.C 3.4).
[4545] Preferably the enzymes are selected from cellulases.
[4546] In one embodiment the hydrolytic enzymes comprise one or more cellulases. The cellulases may be selected from at least the group consisting of an endoglucanase (EG), and a cellobiohydrolase (CBH). More particularly, the cellulase(s) comprisies one or more enzyme selected from the group consisting of an endoglucanase, a cellobiohydrolase I, a cellobiohydrolase II, or a combination thereof.
[4547] In one embodiment the hydrolytic enzymes further comprise an arabinofuranosidase. The arabinofuranosidase may be selected from the group consisting of a GH43 polypeptide, a GH62 polypeptide, GH51 polypeptide. Particularly a GH62 polypeptide.
[4548] In one embodiment, the one or more hydrolytic enzymes is expressed in an organism with a cellulase background, such as Trichoderma reesei. According to these embodiments the xylanase and or arabinofuranosidase polypeptides defined according to the invention is/are expressed together with endogenous cellulases from Trichoderma.
[4549] In one embodiment, the enzyme composition comprising one or more hydrolytic enzymes may comprise cellulases derived from Trichoderma reesei or Humicula insolens. In one particular embodiment the celullases are derived from Trichoderma reesei background cellulases and having a CBH I and CBH II derived from Aspergillus fumigatus.
[4550] In one embodiment, the one or more hydrolytic enzymes are purified. The purified enzymes may be used in an enzyme composition as described in other embodiments of the present invention.
[4551] In one embodiment, the one or more hydrolytic enzymes is/are in a liquid composition. The composition may be homogenous or heterogeneous.
[4552] In one embodiment, the one or more hydrolytic enzymes is/are in a solid composition.
[4553] In one embodiment, the effective amount of one or more hydrolytic enzymes admixed with one or more fractions of said corn kernel mass, is between 0.005-0.5 kg enzyme protein (EP)/metric tonne (MT) corn kernels entering the wet milling process, such as between 0.010-0.5 kg EP/MT corn kernel, such as between 0.05-0.5 kg/MT corn kernel or 0.075-0.5 kg/MT or 0.1-0.5 kg/MT corn kernel or 0.005-0.4 kg/MT corn kernel or 0.01-0.4 kg/MT corn kernel or 0.05-0.4 kg/MT corn kernel or 0.075-0.4 kg/MT corn kernel or 0.1-0.4 kg/MT corn kernel or 0.005-0.3 kg/MT corn kernel or 0.01-0.3 kg/MT corn kernel or 0.05-0.3 kg/MT corn kernel or 0.075-0.3 kg/MT or 0.1-0.3 kg/MT corn kernel or 0.005-0.2 kg/MT corn kernel or 0.010-0.2 kg/MT corn kernel or 0.05-0.2 kg/MT corn kernel or 0.075-0.2 kg/MT or 0.1-0.2 kg/MT corn kernel or such as 0.075-0.10 kg/MT corn kernel or 0.075-0.11 kg/MT corn kernel.
[4554] In preferred embodiments the enzyme composition comprises cellulase obtained from a culture of Trichoderma reesei, such as a culture of Trichoderma reesei ATCC 26921. Suitable cellulases are available; e.g. from Novozymes A/S under the commercial name Celluclast®.
[4555] In a preferred embodiment, said corn kernels or a fraction of said corn kernels is admixed with an enzyme composition comprising comprising a xylanase variant of the present invention and one or more hydrolytic enzymes during the step of subjecting the corn kernel mass to a fiber washing procedure.
[4556] In one embodiment, said corn kernels or a fraction of said corn kernels is allowed to react with said an enzyme composition comprising a xylanase variant and one or more hydrolytic enzymes for at least 15 minutes, such as at least 20 minutes, at least 25 minutes, at least 30 minutes, at least 35 minutes, at least 40 minutes, at least 45 minutes, at least 50 minutes, at least 55 minutes, at least 60 minutes, at least 70 minutes, at least 80 minutes, at least 90 minutes, at least 100 minutes, at least 110 minutes or at least 120 minutes.
[4557] The specific equipment used in the fiber washing procedure can vary, but the main principle of the process remains the same.
[4558] In one embodiment, the incubation temperature in said fiber washing system is between 25 and 95° C., such as between 25 and 90° C., 25 and 85° C., 25 and 80° C., 25 and 75° C., 25 and 70° C., 25 and 65° C., 25 and 60° C., 25 and 55° C., 25 and 53° C., 25 and 52° C., 30 and 90° C., 30 and 85° C., 30 and 80° C., 30 and 75° C., 30 and 70° C., 30 and 65° C., 30 and 60° C., 30 and 55° C., 30 and 53° C., 30 and 52° C., 35 and 90° C., 35 and 85° C., 35 and 80° C., 35 and 75° C., 35 and 70° C., 35 and 65° C., 35 and 60° C., 35 and 55° C., 35 and 53° C., 35 and 52° C., 39 and 90° C., 39 and 85° C., 39 and 80° C., 39 and 75° C., 39 and 70° C., 39 and 65° C., 39 and 60° C., 39 and 55° C., 39 and 53° C., 39 and 52° C.
[4559] In one embodiment, the enzyme composition comprising one or more hydrolytic enzymes may comprise cellulases expressed in Trichoderma reesei and other hydrolotic enzymes which are added to the enzyme composition in a purified or semi-purified form.
[4560] In one embodiment, the one or more hydrolytic enzymes are purified. The purified enzymes may be used in an enzyme composition as described in other embodiments of the present invention.
[4561] In one embodiment, the one or more hydrolytic enzymes is/are in a liquid composition. The composition may be homogenous or heterogeneous.
[4562] In one embodiment, the one or more hydrolytic enzymes is/are in a solid composition.
[4563] The invention is further defined in the following paragraphs:
[4564] Paragraph 1. A xylanase variant of a parent xylanase comprising a substitution at one or more positions corresponding to position 45, 149, 364, 258, 276, and 388 of SEQ ID NO: 1 and wherein said variant has xylanase activity and wherein said variant has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%, but less than 100% sequence identity sequence identity to the polypeptide of SEQ ID NO: 1.
[4565] Paragraph 2. The xylanase variant according to paragraph 1, which has increased thermostability compared to the xylanase of SEQ ID NO: 1.
[4566] Paragraph 3. The xylanase variant according to paragraphs 1-2, wherein said increased thermostability is measured as increased melting temperature using TSA of at least 0.5° C., at least 1° C., at least 1.5° C., at least 2° C., at least 2.5° C., at least 3° C., at least 3.5° C., at least 4.0° C., at least 4.5° C. or at least 5° C.
[4567] Paragraph 4. The xylanase variant according to paragraphs 1-2, wherein said increased thermostability is measured as increased melting temperature using n-DSF of at least 0.5° C., at least 1° C., at least 1.5° C., at least 2° C., at least 2.5° C., at least 3° C., at least 3.5° C., at least 4.0° C., at least 4.5° C. or at least 5° C.
[4568] Paragraph 5. The xylanase variant according to any one of the preceding paragraphs further comprising a substitution at one or more positions corresponding to position to 9, 11, 18, 19, 20, 24, 25, 28, 40, 60, 61, 69, 70, 77, 79, 92, 93, 95, 113, 117, 127, 161, 163, 168, 170, 173, 180, 187, 190, 192, 211, 214, 215, 219, 234, 243, 250, 252, 260, 281, 282, 286, 314, 334, 340, 350, 355, 356, 358, 366, 375, 384, 385, 386, 389, 391, 393, 394, 395, 396, 446, 459, 468, 469, 470, 471, 472, 473, 474, 476, 477, 478, 480, 481, 483, 484, 495, 496, 497, 498, 499, 500, 501, 503, 522, 525, 526, 527, 528, 529, 530, and 540 of SEQ ID NO: 1.
[4569] Paragraph 6. The xylanase variant according to paragraph 5, wherein said variant comprises one or more of the following substitutions at a position corresponding to positions D9E, D11E, A18V, 519T, A20H, A20P, A24H, A24K, A25W, M28P, C40A, C40L, C40S, C40V, C60A, C60L, C60S, C60V, Q61K, Q61R, C69A, C69L, C69S, C69V, T70R, Q77E, A79C, S92D, S92N, A93S, A93T, D95N, D113T, A117C, A117S, N127D, C161L, C161S, C161V, N163H, N168G, A170S, S173Y, T180Q, G187K, G187L, G187S, S190E, D192E, T211H, S214E, S214Q, S214Y, T215I, T215K, T215V, H219I, H219V, V234P, C243L, C243S, C243V, W250Y, A252S, N260H, L281V, S282N, A286E, A286S, Q314A, H334D, A340G, V350L, N355G, L356M, H358D, H358T, T366I, T366V, C375A, C375L, C375S, C375V, Q384A, Q385C, Y386G, S389H, S389V Y391V, V393H, V393R, G394A, G394D, G394Q, N395D, C396A, C396L, C396A, C396S, C396V, D446T, R459V, 0468A, C468L, C468S, C468V, I469T, D470A, D470K, D470T, D470V, L471R, A472I, A472L, S473G, S473K, N474G, N476D, N476N, T477K, T477V, L478N, L478P, T480L, T480N, S481A, R483V, L484D, L484K, L484S, W495E, W495I, W495S, Q496E, Q496W, Q496R, V497D, V497E, V497P, V497W, V498I, A499L, A499Y, V500T, S501E, S501N, G503L, C522A, C522S, C522V, D525L, G526T, N527H, S528H, N529T, L530R, C540A, C540L, C540S, and C540V of SEQ ID NO: 1.
[4570] Paragraph 7. The variant of any of the preceding paragraphs, wherein the variant comprises at least one of the following substitutions or combinations of substitutions:
[4571] V45L;
[4572] V45N;
[4573] V451;
[4574] V45T;
[4575] V45C;
[4576] L149R;
[4577] V258P;
[4578] V258R;
[4579] A276S;
[4580] A276C;
[4581] A276Q;
[4582] A276F;
[4583] A276N;
[4584] A276T;
[4585] A276Y;
[4586] A364G;
[4587] A364A;
[4588] 5388A;
[4589] S388H;
[4590] 5388L;
[4591] S388R;
[4592] V45L+L149R;
[4593] V45N+L149R;
[4594] L149R+A364G;
[4595] V258P+A276Q;
[4596] V258P+A276S;
[4597] A25W+L149R;
[4598] V45 L+A276S;
[4599] A25W+A276S;
[4600] V45 L+A276Q;
[4601] V45L+V258P;
[4602] A25W+V258P;
[4603] A25W+A276Q;
[4604] L149R+W250Y;
[4605] V45 L+S388K;
[4606] V45 L+A364G;
[4607] V45N+V258P;
[4608] V258P+S388K;
[4609] A25W+V45 L;
[4610] A276Q+S388K;
[4611] W250Y+A276Q;
[4612] A276S+S388K;
[4613] A276Q+L281V;
[4614] W250Y+A276S;
[4615] A25W+S388K;
[4616] A276S+L281V;
[4617] G187S+A276Q;
[4618] S92 D+A276S;
[4619] L149R+V258R;
[4620] V45N+S388K;
[4621] A25W+A364G;
[4622] V258P+L281V;
[4623] V258R+A276S;
[4624] G187S+A276S;
[4625] G187K+A276S;
[4626] V45L+S92D;
[4627] V45L+L281V;
[4628] V45N+W250Y;
[4629] V258R+A276Q;
[4630] V45L+V258R;
[4631] W250Y+S388K;
[4632] V45N+G187K;
[4633] A25W+V258R;
[4634] G187K+S388K;
[4635] A25W+S92D;
[4636] L281V+S388K;
[4637] V45N+V258R;
[4638] L281V+A364G;
[4639] S92 D+A364G;
[4640] A25W+G187S;
[4641] A25W+G187K;
[4642] W250Y+V258P;
[4643] S92 D+V258P;
[4644] G187K+W250Y;
[4645] V45N+S92D;
[4646] G187S+A364G;
[4647] G187S+L281V;
[4648] G187S+S388K;
[4649] G187S+V258R;
[4650] S92D+G187S;
[4651] V45L+D11E;
[4652] L149R+S388K;
[4653] L149R+D11E;
[4654] A364G+D11E;
[4655] S388K+D11E;
[4656] V45L+L149R+V258P;
[4657] V45L+L149R+A364G;
[4658] V45L+L149R+W250Y;
[4659] V45L+L149R+G187S;
[4660] V45L+L149R+S282N;
[4661] V45L+S92D+L149R;
[4662] V45L+L149R+A252S+H334D;
[4663] V45L+L149R+S190E+D446T;
[4664] V45L+L149R+V258P+A364G;
[4665] V45L+L149R+A276Q+A364G;
[4666] V45L+L149R+A276S+A364G;
[4667] V45L+L149R+V258P+A276S;
[4668] V45L+L149R+L281V+A364G;
[4669] L149R+V258P+A276S+A364G;
[4670] V45L+V258P+A276S+A364G;
[4671] A25W+V45L+L149R+A364G;
[4672] V45L+L149R+V258R+A364G;
[4673] V45L+L149R+G187K+A364G;
[4674] V45L+L149R+G187S+A364G;
[4675] V45L+L149R+W250Y+A364G;
[4676] V45L+A93S+L149R+A252S+H334D;
[4677] V45L+A93S+L149R+A252S+H334D;
[4678] V45L+A93S+L149R+V234P+A252S;
[4679] V45L+A93S+L149R+A252S+H334D;
[4680] V45L+A93S+L149R+A252S+H334D;
[4681] V45L+A93S+L149R+A252S+H334D;
[4682] V45L+L149R+S190E+D446T+R459V;
[4683] V45L+L149R+V258P+A276S+A364G;
[4684] V45L+L149R+V258P+A276Q+A364G;
[4685] A25W+V45L+L149R+V258P+A276S;
[4686] V45L+L149R+A276Q+L281V+A364G;
[4687] V45 L+L149R+A276Q+S282N+A364G;
[4688] A25W+V45L+L149R+V258P+A276Q;
[4689] V45 L+T70 R+L149R+A276Q+A364G;
[4690] V45L+L149R+V258P+L281V+A364G;
[4691] A25W+V45L+L149R+A276Q+A364G;
[4692] V45L+L149R+A276Q+Q314A+A364G;
[4693] V45L+L149R+G187K+V258P+A364G;
[4694] V45 L+L149R+A276Q+A286E+A364G;
[4695] V45 L+L149R+A276Q+H358T+A364G;
[4696] A25W+V45N+L149R+V258P+A276S;
[4697] V45L+N127D+L149R+A276Q+A364G;
[4698] V45 L+L149R+W250Y+A276Q+A364G;
[4699] V45 L+L149R+W250Y+V258P+A364G;
[4700] V45L+L149R+A276Q+A364G+S388K;
[4701] A25W+V45L+L149R+V258P+A364G;
[4702] V45L+L149R+N168G+A276Q+A364G;
[4703] V45L+A117S+L149R+A276Q+A364G;
[4704] A24K+V45 L+L149R+A276Q+A364G;
[4705] V45 L+L149R+A276Q+A286S+A364G;
[4706] V45 L+L149R+A170S+A276Q+A364G;
[4707] V45L+L149R+T180Q+A276Q+A364G;
[4708] V45 L+L149R+A276Q+V350 L+A364G;
[4709] V45L+L149R+V258P+S282N+A364G;
[4710] A25W+V45L+L149R+A276S+A364G;
[4711] V45L+L149R+G187S+V258P+A364G;
[4712] A25W+L149R+V258P+A276S+A364G;
[4713] V45L+L149R+G187L+A276Q+A364G;
[4714] A25W+V45L+V258P+A276S+A364G;
[4715] V45L+L149R+N260H+A276Q+A364G;
[4716] V45L+L149R+W250Y+V258R+A364G;
[4717] V45L+L149R+N163H+A276Q+A364G;
[4718] V45L+S92D+L149R+A276Q+A364G;
[4719] V45 L+L149R+S173Y+A276Q+A364G;
[4720] V45L+S92D+L149R+V258P+A364G;
[4721] V45L+D113T+L149R+A276Q+A364G;
[4722] V45L+L149R+G187S+V258R+A364G V45L+L149R+V258R+A364G+S388K;
[4723] V45L+L149R+G187K+V258R+A364G;
[4724] V45L+L149R+V258R+S282N+A364G;
[4725] V45L+L149R+V258R+L281V+A364G;
[4726] V45L+S92N+L149R+V258P+A364G;
[4727] V45L+L149R+V258P+A364G+S388K;
[4728] V45L+S92N+L149R+V258R+A364G;
[4729] A25W+V45L+A79C+L149R+V258P+A276S;
[4730] V45 L+L149R+V258P+A276S+H358T+A364G;
[4731] A25W+V45L+L149R+V258P+A276S+A364G;
[4732] V45 L+L149R+V258P+A276S+L281V+A364G;
[4733] V45L+A93S+L149R+A252S+H334D+A340G;
[4734] V45L+L149R+V258P+A276S+A364G+S388K;
[4735] V45L+L149R+N168G+V258P+A276S+A364G;
[4736] V45L+L149R+S173Y+V258P+A276S+A364G;
[4737] V45L+A93S+L149R+A252S+H334D+A340G;
[4738] A25W+V45L+L149R+V258P+A276S+H358T;
[4739] A25W+V45L+L149R+V258P+A276Q+A364G;
[4740] A25W+V45L+L149R+S214E+V258P+A276S;
[4741] V45L+L149R+A170S+V258P+A276S+A364G;
[4742] A25W+V45L+L149R+S214Q+V258P+A276S;
[4743] A25W+V45L+L149R+V258P+A276S+S388K;
[4744] V45L+A93S+L149R+V234P+A252S+H334D;
[4745] V45L+N127D+L149R+V258P+A276S+A364G;
[4746] V45 L+L149R+W250Y+V258P+A276S+A364G;
[4747] A25W+V45L+L149R+W250Y+A276Q+A364G;
[4748] V45L+L149R+T180Q+V258P+A276S+A364G;
[4749] V45 L+L149R+V258P+A276S+Q314A+A364G;
[4750] V45L+A117S+L149R+V258P+A276S+A364G;
[4751] V45N+L149R+V258P+A276S+A364G+S388K;
[4752] V45 L+L149R+V258P+A276Q+L281V+A364G;
[4753] A25W+V45L+L149R+V258P+A276S+Q314A;
[4754] V45 L+L149R+V258P+A276S+A286E+A364G;
[4755] A25W+V45L+L149R+A276Q+L281V+A364G;
[4756] A25W+V45L+L149R+V258P+A276S+A286E;
[4757] A25W+V45L+L149R+V258P+A276S+L281V;
[4758] A25W+V45L+D113T+L149R+V258P+A276S;
[4759] A25W+V45L+L149R+T180Q+V258P+A276S;
[4760] A25W+V45L+L149R+V258P+A276S+A286S;
[4761] V45L+L149R+G187L+A276Q+L281V+A364G;
[4762] V45L+L149R+A276Q+L281V+V350L+A364G;
[4763] V45L+L149R+A276Q+L281V+A364G+S388K;
[4764] A25W+V45L+S92D+L149R+V258P+A276S;
[4765] A25W+V45L+L149R+G187L+V258P+A276S;
[4766] A25W+V45L+L149R+W250Y+V258P+A276S;
[4767] V45L+D113T+L149R+V258P+A276S+A364G;
[4768] V45L+T70R+L149R+A276Q+L281V+A364G;
[4769] V45L+S92D+L149R+A276Q+L281V+A364G;
[4770] V45L+D113T+L149R+A276Q+L281V+A364G;
[4771] V45L+L149R+A276Q+L281V+Q314A+A364G;
[4772] A25W+V45L+Q61K+L149R+V258P+A276S;
[4773] D9E+A25W+V45L+L149R+V258P+A276S;
[4774] V45L+T70R+L149R+V258P+A276S+A364G;
[4775] V45L+L149R+N163H+V258P+A276S+A364G;
[4776] V45L+L149R+T180Q+A276Q+L281V+A364G;
[4777] V45 L+L149R+A276Q+L281V+A286S+A364G;
[4778] A25W+V45L+L149R+A170S+V258P+A276S;
[4779] A25W+V45L+T70R+L149R+V258P+A276S;
[4780] V45L+L149R+N168G+A276Q+L281V+A364G;
[4781] V45 L+L149R+S173Y+A276Q+L281V+A364G;
[4782] V45 L+L149R+W250Y+A276Q+L281V+A364G;
[4783] A25W+V45L+L149R+A276Q+A286E+A364G;
[4784] A25W+V45L+L149R+A276Q+A364G+S388K;
[4785] V45L+N127D+L149R+A276Q+L281V+A364G;
[4786] V45 L+L149R+A276Q+L281V+A286E+A364G;
[4787] A25W+V45L+A117S+L149R+V258P+A276S;
[4788] A24K+V45L+L149R+V258P+A276S+A364G;
[4789] V45L+L149R+V258P+A276S+S282N+A364G;
[4790] V45L+A117S+L149R+A276Q+L281V+A364G;
[4791] V45L+L149R+N260H+A276Q+L281V+A364G;
[4792] A25W+V45L+L149R+N168G+V258P+A276S;
[4793] A25W+V45L+L149R+G187S+V258P+A276S;
[4794] A25W+V45L+L149R+V258P+A276S+V350L;
[4795] A25W+V45L+Q61R+L149R+V258P+A276S;
[4796] V45N+L149R+V258P+A276S+L281V+A364G;
[4797] A25W+V45L+L149R+V258P+A276S+S282N;
[4798] A25W+V45L+L149R+S173Y+V258P+A276S;
[4799] A25W+V45L+L149R+A276Q+A286S+A364G;
[4800] A25W+V45L+L149R+T215V+V258P+A276S;
[4801] A25W+V45L+L149R+T215I+V258P+A276S;
[4802] A25W+V45L+L149R+T211H+V258P+A276S;
[4803] V45 L+L149R+V258P+A276S+V350L+A364G;
[4804] A25W+V45L+D113T+L149R+A276Q+A364G;
[4805] A25W+V45N+L149R+V258P+A276S+A364G;
[4806] A25W+V45L+L149R+H219I+V258P+A276S;
[4807] M28P+V45L+L149R+V258P+A276S+A364G;
[4808] A25W+V45L+T70 R+L149R+A276Q+A364G;
[4809] A25W+V45L+L149R+A276Q+Q314A+A364G;
[4810] A25W+V45L+L149R+S214Y+V258P+A276S;
[4811] V45L+L149R+A276Q+L281V+H358T+A364G;
[4812] A25W+V45L+L149R+H219V+V258P+A276S;
[4813] D11E+A25W+V45L+L149R+V258P+A276S;
[4814] A25W+V45L+A117S+L149R+A276Q+A364G;
[4815] A25W+V45L+L149R+G187L+A276Q+A364G;
[4816] V45N+L149R+V258P+A276S+H358T+A364G;
[4817] A25W+V45L+L149R+N163H+A276Q+A364G;
[4818] A25W+V45L+L149R+S173Y+A276Q+A364G;
[4819] A25W+V45L+L149R+A276Q+S282N+A364G;
[4820] A25W+V45L+L149R+A276Q+H358T+A364G;
[4821] A25W+V45L+L149R+T180Q+A276Q+A364G;
[4822] A25W+V45L+N127D+L149R+A276Q+A364G;
[4823] A25W+V45L+L149R+A170S+A276Q+A364G;
[4824] A25W+V45L+N127D+L149R+V258P+A276S;
[4825] A25W+V45L+L149R+N168G+A276Q+A364G;
[4826] A25W+V45L+L149R+N260H+A276Q+A364G;
[4827] A25W+V45L+L149R+G187K+V258P+A276S;
[4828] A25W+M28P+V45L+L149R+V258P+A276S;
[4829] V45L+L149R+N163H+A276Q+L281V+A364G;
[4830] V45L+L149R+G187L+V258P+A276S+A364G;
[4831] A25W+V45 L+L149R+A276Q+V350L+A364G;
[4832] V45L+L149R+V258P+A276S+N355G+A364G;
[4833] A25W+V45L+L149R+V258P+A276S+N355G;
[4834] A25W+V45L+S92D+L149R+A276Q+A364G;
[4835] A25W+V45L+L149R+A276Q+N355G+A364G;
[4836] V45L+A79C+L149R+V258P+A276S+A364G+S388K;
[4837] V45N+A79C+L149R+V258P+A276S+A364G+S388K;
[4838] V45L+L149R+S214Q+V258P+A276S+H358D+A364G;
[4839] A25W+V45L+A79C+L149R+V258P+A276S+A364G;
[4840] V45L+A79C+L149R+V258P+A276S+L281V+A364G;
[4841] A25W+V45L+L149R+S214E+V258P+A276S+A364G;
[4842] V45L+L149R+S214Q+V258P+A276Q+A364G+S388K;
[4843] V45N+L149R+S214Q+V258P+A276S+A364G+S388K;
[4844] V45L+L149R+S214Q+V258P+A276S+A364G+S388K;
[4845] V45L+L149R+S214E+V258P+A276S+H358T+A364G;
[4846] A25W+V45L+L149R+S214E+V258P+A276Q+A364G;
[4847] V45L+L149R+S214Q+V258P+A276S+L281V+A364G;
[4848] V45L+N127D+L149R+V258P+A276S+A364G+S388K;
[4849] V45L+L149R+V258P+A276S+H358T+A364G+S388K;
[4850] V45L+L149R+G187L+V258P+A276S+A364G+S388K;
[4851] V45L+L149R+W250Y+V258P+A276S+A364G+S388K;
[4852] V45L+L149R+V258P+A276S+A286E+A364G+S388K;
[4853] V45L+L149R+V258P+A276S+S282N+A364G+S388K;
[4854] A25W+V45L+L149R+V258P+A276S+A364G+S388K;
[4855] V45L+L149R+S214Q+V258P+A276S+H358T+A364G;
[4856] A25W+V45L+L149R+S214Q+V258P+A276S+A364G;
[4857] V45L+L149R+N168G+V258P+A276S+A364G+S388K;
[4858] V45L+A117S+L149R+V258P+A276S+A364G+S388K;
[4859] A25W+V45L+L149R+V258P+A276S+H358T+A364G;
[4860] V45L+L149R+V258P+N260H+A276S+A364G+S388K;
[4861] V45L+L149R+T215I+V258P+A276S+A364G+S388K;
[4862] V45L+Q61K+L149R+V258P+A276S+H358T+A364G;
[4863] V45L+L149R+V258P+A276S+Q314A+H358T+A364G;
[4864] V45L+L149R+T180Q+V258P+A276S+A364G+S388K;
[4865] V45L+L149R+V258P+A276S+Q314A+A364G+S388K;
[4866] A25W+V45L+L149R+V258P+A276S+A286S+A364G;
[4867] V45L+L149R+H219I+V258P+A276S+H358T+A364G;
[4868] V45L+L149R+V258P+A276S+V350L+A364G+S388K;
[4869] D11E+V45L+L149R+V258P+A276S+A364G+S388K;
[4870] V45L+D113T+L149R+V258P+A276S+A364G+S388K;
[4871] V45L+L149R+G187K+V258P+A276S+A364G+S388K;
[4872] M28P+V45L+L149R+V258P+A276S+A364G+S388K;
[4873] V45L+L149R+S173Y+V258P+A276S+A364G+S388K;
[4874] A25W+V45L+L149R+V258P+A276S+Q314A+A364G;
[4875] V45L+L149R+G187L+V258P+A276S+H358T+A364G;
[4876] V45L+L149R+T215V+V258P+A276S+H358T+A364G;
[4877] V45L+T70R+L149R+V258P+A276S+A364G+S388K;
[4878] V45L+L149R+V258P+A276S+V350L+H358T+A364G;
[4879] D9E+V45L+L149R+V258P+A276S+H358T+A364G;
[4880] V45L+L149R+T211H+V258P+A276S+H358T+A364G;
[4881] V45L+L149R+V258P+A276S+L281V+A364G+S388K;
[4882] V45L+L149R+V258P+A276S+S282N+H358T+A364G;
[4883] V45L+L149R+T215I+V258P+A276S+H358T+A364G;
[4884] A25W+V45L+L149R+S173Y+V258P+A276S+A364G;
[4885] V45L+Q61K+L149R+V258P+A276S+A364G+S388K;
[4886] A25W+V45L+Q61K+L149R+V258P+A276S+A364G;
[4887] V45L+L149R+S214E+V258P+A276S+L281V+A364G;
[4888] V45 L+L149R+V258P+A276S+A286E+H358T+A364G;
[4889] D9E+V45L+L149R+V258P+A276S+A364G+S388K;
[4890] V45L+S92D+L149R+V258P+A276S+A364G+S388K;
[4891] A25W+V45L+L149R+V258P+A276S+A286E+A364G;
[4892] V45L+L149R+N168G+V258P+A276S+L281V+A364G;
[4893] V45L+Q61R+L149R+V258P+A276S+H358T+A364G;
[4894] V45L+L149R+G187S+V258P+A276S+A364G+S388K;
[4895] V45L+L149R+V258P+A276S+L281V+Q314A+A364G;
[4896] V45L+L149R+V258P+A276S+L281V+H358T+A364G;
[4897] V45L+L149R+A170S+V258P+A276S+H358T+A364G;
[4898] V45L+L149R+A170S+V258P+A276S+A364G+S388K;
[4899] V45L+L149R+T215V+V258P+A276S+A364G+S388K;
[4900] V45L+L149R+V258P+A276Q+H358T+A364G+S388K;
[4901] A25W+V45N+L149R+S214E+V258P+A276S+A364G;
[4902] V45 L+L149R+V258P+A276S+A286S+H358T+A364G;
[4903] A25W+V45L+L149R+G187S+V258P+A276S+A364G;
[4904] V45L+L149R+T180Q+V258P+A276S+L281V+A364G;
[4905] V45L+S92D+L149R+V258P+A276S+L281V+A364G;
[4906] V45L+Q61R+L149R+V258P+A276S+L281V+A364G;
[4907] V45L+L149R+A170S+V258P+A276S+L281V+A364G;
[4908] D11E+A25W+V45L+L149R+V258P+A276S+A364G;
[4909] A25W+V45L+Q61R+L149R+V258P+A276S+A364G;
[4910] A25W+V45L+L149R+T215V+V258P+A276S+A364G;
[4911] D9E+V45L+L149R+V258P+A276S+L281V+A364G;
[4912] A25W+V45L+L149R+V258P+A276S+V350L+A364G;
[4913] V45L+L149R+H219V+V258P+A276S+L281V+A364G;
[4914] V45L+L149R+T180Q+V258P+A276S+H358T+A364G;
[4915] V45L+L149R+T215V+V258P+A276S+L281V+A364G;
[4916] A25W+V45L+L149R+V258P+A276S+S282N+A364G;
[4917] A25W+V45L+L149R+T215I+V258P+A276S+A364G;
[4918] A25W+V45L+L149R+H219I+V258P+A276S+A364G;
[4919] V45L+A117S+L149R+V258P+A276S+L281V+A364G;
[4920] D9E+A25W+V45L+L149R+V258P+A276S+A364G;
[4921] V45L+L149R+S214Y+V258P+A276S+A364G+S388K;
[4922] A25W+V45L+L149R+T180Q+V258P+A276S+A364G;
[4923] A25W+V45L+L149R+V258P+A276S+L281V+A364G;
[4924] V45L+N127D+L149R+V258P+A276S+L281V+A364G;
[4925] V45L+L149R+S173Y+V258P+A276S+H358T+A364G;
[4926] V45L+Q61R+L149R+V258P+A276S+A364G+S388K;
[4927] V45 L+L149R+V258P+A276S+L281V+A286E+A364G;
[4928] A25W+V45L+L149R+W250Y+V258P+A276S+A364G;
[4929] A25W+V45L+L149R+V258P+N260H+A276S+A364G;
[4930] V45 L+L149R+V258P+A276S+L281V+V350L+A364G;
[4931] A25W+V45L+L149R+A170S+V258P+A276S+A364G;
[4932] V45 L+L149R+V258P+A276S+L281V+A286S+A364G;
[4933] V45L+L149R+V258P+A276S+L281V+S282N+A364G;
[4934] D11E+V45L+L149R+V258P+A276S+L281V+A364G;
[4935] V45L+Q61K+L149R+V258P+A276S+L281V+A364G;
[4936] V45L+L149R+T215I+V258P+A276S+L281V+A364G;
[4937] A25W+V45L+S92D+L149R+V258P+A276S+A364G;
[4938] V45L+L149R+S214Y+V258P+A276S+L281V+A364G;
[4939] V45L+L149R+T211H+V258P+A276S+L281V+A364G;
[4940] A25W+V45L+L149R+G187L+V258P+A276S+A364G;
[4941] V45L+S92D+L149R+V258P+A276S+H358T+A364G;
[4942] V45L+L149R+G187K+V258P+A276S+H358T+A364G;
[4943] V45L+L149R+N163H+V258P+A276S+L281V+A364G;
[4944] A25W+V45L+T70R+L149R+V258P+A276S+A364G;
[4945] V45L+L149R+S173Y+V258P+A276S+L281V+A364G;
[4946] V45L+L149R+G187L+V258P+A276S+L281V+A364G;
[4947] V45L+L149R+G187K+V258P+A276S+L281V+A364G;
[4948] V45 L+L149R+W250Y+V258P+A276S+H358T+A364G;
[4949] V45L+L149R+T211H+V258P+A276S+A364G+S388K;
[4950] V45L+L149R+N163H+V258P+A276S+A364G+S388K;
[4951] V45 L+L149R+V258P+A276S+A286S+A364G+S388K;
[4952] A25W+V45L+L149R+S214Y+V258P+A276S+A364G;
[4953] A25W+V45L+D113T+L149R+V258P+A276S+A364G;
[4954] V45L+T70R+L149R+V258P+A276S+L281V+A364G;
[4955] A25W+V45L+N127D+L149R+V258P+A276S+A364G;
[4956] V45 L+T70R+L149R+V258P+A276S+H358T+A364G;
[4957] V45L+L149R+H219I+V258P+A276S+L281V+A364G;
[4958] A25W+V45L+A117S+L149R+V258P+A276S+A364G;
[4959] A25W+V45L+L149R+N168G+V258P+A276S+A364G;
[4960] V45L+N127D+L149R+V258P+A276S+H358T+A364G;
[4961] A25W+V45L+L149R+H219V+V258P+A276S+A364G;
[4962] D11E+V45L+L149R+V258P+A276S+H358T+A364G;
[4963] V45L+L149R+G187S+V258P+A276S+L281V+A364G;
[4964] A25W+V45L+L149R+N163H+V258P+A276S+A364G;
[4965] A25W+V45L+L149R+G187K+V258P+A276S+A364G;
[4966] V45L+L149R+V258P+N260H+A276S+H358T+A364G;
[4967] V45L+D113T+L149R+V258P+A276S+L281V+A364G;
[4968] V45L+D113T+L149R+V258P+A276S+H358T+A364G;
[4969] V45L+L149R+N168G+V258P+A276S+H358T+A364G;
[4970] V45L+L149R+S214Y+V258P+A276S+H358T+A364G;
[4971] V45L+A117S+L149R+V258P+A276S+H358T+A364G;
[4972] A25W+M28P+V45L+L149R+V258P+A276S+A364G;
[4973] M28P+V45L+L149R+V258P+A276S+L281V+A364G;
[4974] M28P+V45L+L149R+V258P+A276S+H358T+A364G;
[4975] V45L+L149R+N163H+V258P+A276S+H358T+A364G;
[4976] V45L+L149R+T215K+V258P+A276S+H358T+A364G;
[4977] V45L+L149R+H219I+V258P+A276S+A364G+S388K;
[4978] V45L+L149R+T215K+V258P+A276S+A364G+S388K;
[4979] V45L+L149R+W250Y+V258P+A276S+L281V+A364G;
[4980] V45L+L149R+H219V+V258P+A276S+A364G+S388K;
[4981] A25W+V45L+L149R+V258P+A276S+N355G+A364G;
[4982] V45L+L149R+V258P+A276S+N355G+A364G+S388K;
[4983] V45L+L149R+V258P+A276S+L281V+N355G+A364G;
[4984] V45 L+L149R+V258P+A276S+N355G+H358T+A364G;
[4985] V45L+L149R+H219V+V258P+A276S+H358T+A364G;
[4986] V45L+A79C+L149R+S214E+V258P+A276S+A364G+S388K;
[4987] V45L+A79C+L149R+S214Q+V258P+A276S+A364G+S388K;
[4988] V45L+A79C+L149R+V258P+A276S+Q314A+A364G+S388K;
[4989] V45L+A79C+L149R+V258P+A276S+L281V+A364G+S388K;
[4990] V45L+A79C+L149R+S173Y+V258P+A276S+A364G+S388K;
[4991] V45L+A79C+L149R+G187K+V258P+A276S+A364G+S388K;
[4992] V45L+Q61R+A79C+L149R+V258P+A276S+A364G+S388K;
[4993] V45L+A79C+L149R+N168G+V258P+A276S+A364G+S388K;
[4994] V45L+A79C+L149R+T215V+V258P+A276S+A364G+S388K;
[4995] V45L+A79C+L149R+V258P+A276S+A286S+A364G+S388K;
[4996] V45L+A79C+L149R+H219V+V258P+A276S+A364G+S388K;
[4997] V45L+A79C+L149R+A170S+V258P+A276S+A364G+S388K;
[4998] D11E+V45L+A79C+L149R+V258P+A276S+A364G+S388K;
[4999] V45L+A79C+L149R+V258P+A276S+A286E+A364G+S388K;
[5000] V45L+A79C+L149R+T180Q+V258P+A276S+A364G+S388K;
[5001] V45L+A79C+L149R+H219I+V258P+A276S+A364G+S388K;
[5002] V45L+L149R+S214E+V258P+A276S+H358D+A364G+D470T;
[5003] V45L+A79C+L149R+V258P+A276S+V350L+A364G+S388K;
[5004] V45L+L149R+S214E+V258P+A276S+H358D+A364G+D470T;
[5005] V45L+A79C+D113T+L149R+V258P+A276S+A364G+S388K;
[5006] V45L+A79C+N127D+L149R+V258P+A276S+A364G+S388K;
[5007] D9E+V45L+A79C+L149R+V258P+A276S+A364G+S388K;
[5008] V45L+L149R+S214E+V258P+A276S+H358D+A364G+D470T;
[5009] V45L+A79C+L149R+W250Y+V258P+A276S+A364G+S388K;
[5010] V45L+L149R+S214E+V258P+A276S+H358D+A364G+D470T;
[5011] V45L+L149R+S214E+V258P+A276S+H358D+A364G+D470T;
[5012] V45L+A79C+L149R+N163H+V258P+A276S+A364G+S388K;
[5013] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G;
[5014] A25W+V45L+A79C+L149R+S214E+V258P+A276S+A364G;
[5015] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+D470T;
[5016] V45L+A79C+S92D+L149R+V258P+A276S+A364G+S388K;
[5017] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G;
[5018] V45L+L149R+S214Q+V258P+A276S+A286E+A364G+S388K;
[5019] V45L+L149R+S214Q+T215I+V258P+A276S+A364G+S388K;
[5020] A25W+V45L+L149R+S214Q+V258P+A276S+A364G+S388K;
[5021] V45L+L149R+A170S+S214Q+V258P+A276S+A364G+S388K;
[5022] V45L+Q61K+L149R+S214Q+V258P+A276S+A364G+S388K;
[5023] V45L+L149R+N168G+S214Q+V258P+A276S+A364G+S388K;
[5024] V45L+A79C+D95D+L149R+V258P+A276S+A364G+S388K;
[5025] V45L+Q77E+A79C+L149R+V258P+A276S+A364G+S388K;
[5026] V45L+L149R+S214Q+V258P+A276S+S282N+A364G+S388K;
[5027] V45L+L149R+S214Q+V258P+A276S+Q314A+A364G+S388K;
[5028] V45L+T70R+L149R+S214Q+V258P+A276S+A364G+S388K;
[5029] V45L+L149R+S214Q+W250Y+V258P+A276S+A364G+S388K;
[5030] V45L+L149R+G187K+S214Q+V258P+A276S+A364G+S388K;
[5031] V45L+L149R+V258P+A276S+L281V+H358T+A364G+S388K;
[5032] M28P+V45L+L149R+S214Q+V258P+A276S+A364G+S388K;
[5033] V45L+L149R+G187L+S214Q+V258P+A276S+A364G+S388K;
[5034] V45L+L149R+S214Q+V258P+A276S+A286S+A364G+S388K;
[5035] D9E+V45L+L149R+S214Q+V258P+A276S+A364G+S388K;
[5036] V45L+L149R+S173Y+S214Q+V258P+A276S+A364G+S388K;
[5037] V45L+A79C+L149R+V258P+A276S+H358T+A364G+S388K;
[5038] A25W+V45L+L149R+S214E+V258P+A276S+H358T+A364G;
[5039] A25W+V45L+L149R+S214E+V258P+A276S+A286E+A364G;
[5040] A25W+V45L+Q61K+L149R+S214E+V258P+A276S+A364G;
[5041] A25W+V45L+L149R+V258P+A276S+H358T+A364G+S388K;
[5042] V45L+L149R+S214Q+V258P+A276S+V350L+A364G+S388K;
[5043] D11E+V45L+L149R+S214Q+V258P+A276S+A364G+S388K;
[5044] V45L+L149R+H219I+V258P+A276S+H358T+A364G+S388K;
[5045] V45L+S92D+L149R+S214Q+V258P+A276S+A364G+S388K;
[5046] A25W+V45L+L149R+T211H+S214E+V258P+A276S+A364G;
[5047] A25W+V45L+L149R+S214E+H219V+V258P+A276S+A364G;
[5048] V45L+L149R+W250Y+V258P+A276S+H358T+A364G+S388K;
[5049] D9E+V45L+L149R+V258P+A276S+H358T+A364G+S388K;
[5050] V45L+L149R+H219V+V258P+A276S+H358T+A364G+S388K;
[5051] V45L+A117S+L149R+S214E+V258P+A276S+A364G+S388K;
[5052] D11E+A25W+V45L+L149R+S214E+V258P+A276S+A364G;
[5053] V45L+L149R+V258P+A276S+Q314A+H358T+A364G+S388K;
[5054] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388L;
[5055] V45L+L149R+T180Q+S214Q+V258P+A276S+A364G+S388K;
[5056] V45L+D113T+L149R+S214Q+V258P+A276S+A364G+S388K;
[5057] A25W+V45L+Q61R+L149R+S214E+V258P+A276S+A364G;
[5058] A25W+V45L+L149R+S214E+V258P+A276S+L281V+A364G;
[5059] D9E+A25W+V45L+L149R+S214E+V258P+A276S+A364G;
[5060] V45L+Q61R+L149R+V258P+A276S+H358T+A364G+S388K;
[5061] V45L+D113T+L149R+V258P+A276S+H358T+A364G+S388K;
[5062] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388R;
[5063] V45L+Q61R+L149R+S214Q+V258P+A276S+A364G+S388K;
[5064] V45L+A117S+L149R+S214Q+V258P+A276Q+A364G+S388K;
[5065] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K;
[5066] V45L+L149R+T180Q+V258P+A276S+H358T+A364G+S388K;
[5067] A25W+V45L+S92D+L149R+S214E+V258P+A276S+A364G;
[5068] A25W+V45L+L149R+S214E+V258P+A276S+V350L+A364G;
[5069] V45L+L149R+T211H+S214Q+V258P+A276S+A364G+S388K;
[5070] A25W+V45L+L149R+S214E+H219I+V258P+A276S+A364G;
[5071] V45L+L149R+T211H+V258P+A276S+H358T+A364G+S388K;
[5072] A25W+V45L+A117S+L149R+S214E+V258P+A276S+A364G;
[5073] A25W+V45L+L149R+S214E+T215V+V258P+A276S+A364G;
[5074] V45L+A117S+L149R+V258P+A276S+H358T+A364G+S388K;
[5075] V45L+L149R+N168G+V258P+A276S+H358T+A364G+S388K;
[5076] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388H;
[5077] A25W+V45L+L149R+S214E+T215I+V258P+A276S+A364G;
[5078] V45L+N127D+L149R+V258P+A276S+H358T+A364G+S388K;
[5079] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388A;
[5080] V45N+A117S+L149R+S214Q+V258P+A276S+A364G+S388K;
[5081] A25W+V45L+L149R+G187S+S214E+V258P+A276S+A364G;
[5082] V45L+A117S+L149R+S214Y+V258P+A276S+A364G+S388K;
[5083] A25W+V45L+L149R+S214E+V258P+A276S+A286S+A364G;
[5084] V45L+L149R+V258P+A276S+A286S+H358T+A364G+S388K;
[5085] V45L+L149R+S173Y+V258P+A276S+H358T+A364G+S388K;
[5086] V45L+A79C+L149R+V258P+A276S+N355G+A364G+S388K;
[5087] A25W+V45L+L149R+G187L+S214E+V258P+A276S+A364G;
[5088] V45L+L149R+S214Q+V258P+A276S+L281V+A364G+S388K;
[5089] V45L+L149R+S214Q+T215V+V258P+A276S+A364G+S388K;
[5090] V45L+L149R+N163H+V258P+A276S+H358T+A364G+S388K;
[5091] V45L+A79C+A117S+L149R+V258P+A276S+A364G+S388K;
[5092] V45L+L149R+A170S+V258P+A276S+H358T+A364G+S388K;
[5093] A25W+V45L+L149R+S214E+T215K+V258P+A276S+A364G;
[5094] V45L+S92D+L149R+V258P+A276S+H358T+A364G+S388K;
[5095] V45L+L149R+S214Q+V258P+A276S+N355G+A364G+S388K;
[5096] A25W+V45L+L149R+S214E+V258P+A276S+N355G+A364G;
[5097] A25W+V45L+L149R+S214E+V258P+A276S+Q314A+A364G;
[5098] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388R+D470T;
[5099] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T;
[5100] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388L+D470T;
[5101] V45L+A117S+L149R+S214Q+V258P+A276Q+A364G+S388K+D470T;
[5102] V45L+A117S+L149R+D192E+S214Q+V258P+A276S+H358D+A364G;
[5103] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388A+D470T;
[5104] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388H+D470T;
[5105] V45N+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T;
[5106] V45L+A117S+L149R+S214E+V258P+A276S+H358D+A364G+S388K;
[5107] V45L+A117S+L149R+D192E+S214Q+V258P+A276S+H358D+A364G;
[5108] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K;
[5109] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+R483V;
[5110] V45L+A117S+L149R+S214E+V258P+A276S+A364G+S388K+D470T;
[5111] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388R;
[5112] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388A;
[5113] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+Q384A+S388K;
[5114] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388L;
[5115] V45L+A117S+L149R+S214Q+V258P+A276S+A286E+A364G+S388K;
[5116] V45L+A117S+L149R+S214Q+V258P+A276S+L281V+A364G+S388K;
[5117] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+G394D;
[5118] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+S473G;
[5119] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+G394A;
[5120] V45N+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K;
[5121] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+L478P;
[5122] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+S481A;
[5123] V45L+A117S+L149R+S214Q+V258P+A276S+Q314A+A364G+S388K;
[5124] V45L+A117S+L149R+S214Q+V258P+A276Q+H358D+A364G+S388K;
[5125] V45L+A117S+L149R+G187K+S214Q+V258P+A276S+A364G+S388K;
[5126] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+L478N;
[5127] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+V393R;
[5128] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+T366V+S388K;
[5129] V45L+A117S+L149R+S214Q+V258P+A276S+H358T+A364G+S388K;
[5130] D11E+V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K;
[5131] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+G394Q;
[5132] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+N395D;
[5133] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+V393H;
[5134] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+S501E;
[5135] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+S528H;
[5136] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388H;
[5137] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+S389H;
[5138] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+T366I+S388K;
[5139] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+N474G;
[5140] V45L+A117S+L149R+S214Y+V258P+A276S+H358D+A364G+S388K;
[5141] V45L+A117S+L149R+S214Q+V258P+A276S+A286S+A364G+S388K;
[5142] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+A499Y;
[5143] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+V500V;
[5144] V45L+A117S+L149R+S214Q+W250Y+V258P+A276S+A364G+S388K;
[5145] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+T480N;
[5146] V45L+A117S+L149R+G187S+S214Q+V258P+A276S+A364G+S388K;
[5147] A25W+V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K;
[5148] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+N476N;
[5149] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+N476D;
[5150] D9E+V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K;
[5151] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+S481S;
[5152] V45L+A117S+L149R+S214Q+H219V+V258P+A276S+A364G+S388K;
[5153] V45L+A117S+L149R+S214Q+T215I+V258P+A276S+A364G+S388K;
[5154] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+Q496R;
[5155] V45L+A117S+L149R+A170S+S214Q+V258P+A276S+A364G+S388K;
[5156] V45L+Q61R+A117S+L149R+S214Q+V258P+A276S+A364G+S388K;
[5157] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+V497P;
[5158] V45L+A117S+L149R+T180Q+S214Q+V258P+A276S+A364G+S388K;
[5159] V45L+A117S+L149R+S214Q+T215V+V258P+A276S+A364G+S388K;
[5160] V45L+A117S+L149R+S214Q+V258P+A276S+V350L+A364G+S388K;
[5161] V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+A364G+S388K;
[5162] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+Y391V;
[5163] V45L+A117S+L149R+N168G+S214Q+V258P+A276S+A364G+S388K;
[5164] V45L+D113T+A117S+L149R+S214Q+V258P+A276S+A364G+S388K;
[5165] M28P+V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K;
[5166] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+T477K;
[5167] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+S389V;
[5168] V45L+A117S+L149R+S173Y+S214Q+V258P+A276S+A364G+S388K;
[5169] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+V500T;
[5170] V45L+A117S+L149R+T211H+S214Q+V258P+A276S+A364G+S388K;
[5171] V45L+S92D+A117S+L149R+S214Q+V258P+A276S+A364G+S388K;
[5172] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+A472L;
[5173] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+S473K;
[5174] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+A499L;
[5175] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+V498I;
[5176] V45L+A117S+L149R+N163H+S214Q+V258P+A276S+A364G+S388K;
[5177] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+N527H;
[5178] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+T477V;
[5179] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+G503L;
[5180] V45L+A117S+L149R+G187L+S214Q+V258P+A276S+A364G+S388K;
[5181] V45L+A117S+L149R+S214Q+T215K+V258P+A276S+A364G+S388K;
[5182] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+Q385C+S388K;
[5183] V45L+A117S+L149R+S214Q+V258P+A276S+N355G+A364G+S388K;
[5184] V45L+A117S+L149R+S214E+V258P+A276S+H358D+A364G+S388K+D470T;
[5185] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388R+D470T;
[5186] V45L+A117S+L149R+S214Q+V258P+A276Q+H358D+A364G+S388K+D470T;
[5187] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388H+D470T;
[5188] V45L+A79C+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K;
[5189] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388L+D470T;
[5190] V45L+A117S+L149R+S214E+V258P+A276S+A364G+S388K+D470T+R483V;
[5191] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388R+D470T+R483V;
[5192] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470A+R483V;
[5193] V45L+A117S+L149R+S214Q+V258P+A276Q+A364G+S388K+D470T+R483V;
[5194] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V;
[5195] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[5196] V45N+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V;
[5197] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388H+D470T+R483V;
[5198] V45L+A79C+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T;
[5199] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388A+D470T;
[5200] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388A+D470T+R483V;
[5201] V45L+A117S+L149R+S214Q+V258P+A276S+L281V+A364G+S388K+D470T;
[5202] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+Q384A+S388K+D470T;
[5203] V45L+A117S+L149R+S214Q+V258P+A276S+A286E+A364G+S388K+D470T;
[5204] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+T477K;
[5205] V45L+A117S+L149R+S214Y+V258P+A276S+H358D+A364G+S388K+D470T;
[5206] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+G394A+D470T;
[5207] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+N476D;
[5208] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+V393H+D470T;
[5209] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+N395D+D470T;
[5210] V45L+A117S+L149R+S214Q+V258P+A276S+H358T+A364G+S388K+D470T;
[5211] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+L478N;
[5212] V45L+A117S+L149R+S214Q+W250Y+V258P+A276S+A364G+S388K+D470T;
[5213] V45L+A117S+L149R+G187L+S214Q+V258P+A276S+A364G+S388K+D470T;
[5214] D9E+V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T;
[5215] V45L+A117S+L149R+S214Q+V258P+A276S+S282N+A364G+S388K+D470T;
[5216] D11E+V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T;
[5217] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+N476N;
[5218] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+G394D+D470T;
[5219] V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T;
[5220] V45L+A117S+L149R+S214Q+V258P+A276S+A286S+A364G+S388K+D470T;
[5221] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470A;
[5222] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+G394Q+D470T;
[5223] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+L478P;
[5224] V45L+A117S+L149R+S214Q+V258P+A276S+V350L+A364G+S388K+D470T;
[5225] V45L+D113T+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T;
[5226] V45L+A117S+L149R+T180Q+S214Q+V258P+A276S+A364G+S388K+D470T;
[5227] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+S389H+D470T;
[5228] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+V393R+D470T;
[5229] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+Q496R;
[5230] V45L+A117S+N127D+L149R+S214Q+V258P+A276S+A364G+S388K+D470T;
[5231] V45 L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+A499Y;
[5232] V45L+A117S+L149R+S173Y+S214Q+V258P+A276S+A364G+S388K+D470T;
[5233] V45L+S92D+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T;
[5234] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+N529T;
[5235] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+L478N;
[5236] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T;
[5237] M28P+V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T;
[5238] V45L+A117S+L149R+S214Y+V258P+A276S+A364G+S388K+D470T+R483V;
[5239] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+N395D;
[5240] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+T477K;
[5241] V45L+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K;
[5242] V45L+Q61R+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T;
[5243] V45L+A117S+L149R+S214Q+T215I+V258P+A276S+A364G+S388K+D470T;
[5244] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+Q496E;
[5245] V45L+A117S+L149R+G187K+S214Q+V258P+A276S+A364G+S388K+D470T;
[5246] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+W495I;
[5247] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+V498I;
[5248] V45 L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+V500V;
[5249] D11E+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K;
[5250] V45L+A117S+L149R+A170S+S214Q+V258P+A276S+A364G+S388K+D470T;
[5251] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+Y391V+D470T;
[5252] V45L+A117S+L149R+S214Q+V258P+A276S+Q314A+A364G+S388K+D470T;
[5253] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+T477V;
[5254] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394Q;
[5255] V45L+A117S+L149R+S214Q+H219V+V258P+A276S+A364G+S388K+D470T;
[5256] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+Q496Q;
[5257] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+A499Y;
[5258] V45L+A117S+L149R+S214Q+T215V+V258P+A276S+A364G+S388K+D470T;
[5259] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+Q385C+S388K+D470T;
[5260] V45 L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+T480N;
[5261] V45 L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+V497P;
[5262] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+A499L;
[5263] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+S501N;
[5264] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+Q384A+S388K;
[5265] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388L+D470T+R483V;
[5266] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394A;
[5267] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+V498I;
[5268] V45L+A117S+L149R+S214Q+H219I+V258P+A276S+A364G+S388K+D470T;
[5269] V45L+A117S+L149R+N163H+S214Q+V258P+A276S+A364G+S388K+D470T;
[5270] V45L+A117S+L149R+S214Q+V258P+A276S+Q314A+H358D+A364G+S388K;
[5271] V45L+A117S+L149R+S173Y+S214Q+V258P+A276S+H358D+A364G+S388K;
[5272] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394D;
[5273] V45L+Q61R+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K;
[5274] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+T366V+S388K;
[5275] V45L+A117S+L149R+T180Q+S214Q+V258P+A276S+H358D+A364G+S388K;
[5276] V45L+A117S+L149R+S214Q+T215I+V258P+A276S+H358D+A364G+S388K;
[5277] V45L+A117S+L149R+S214Q+W250Y+V258P+A276S+H358D+A364G+S388K;
[5278] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+N476D;
[5279] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+T477V;
[5280] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+L478P;
[5281] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S481A;
[5282] V45L+A117S+L149R+T211H+S214Q+V258P+A276S+A364G+S388K+D470T;
[5283] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+V500T;
[5284] V45L+A117S+L149R+S214Q+V258P+A276S+V350L+H358D+A364G+S388K;
[5285] V45L+A117S+L149R+G187K+S214Q+V258P+A276S+H358D+A364G+S388K;
[5286] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470V+R483V;
[5287] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+V500V;
[5288] V45L+A117S+L149R+N163H+S214Q+V258P+A276S+H358D+A364G+S388K;
[5289] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S481S;
[5290] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+V500T;
[5291] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+W495S;
[5292] V45L+D113T+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K;
[5293] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+N474G;
[5294] V45L+A117S+L149R+S214Q+V258P+A276S+S282N+H358D+A364G+S388K;
[5295] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+Q496Q;
[5296] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+S389V+D470T;
[5297] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S501E;
[5298] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+N476N;
[5299] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S473K;
[5300] V45L+A117S+L149R+G187L+S214Q+V258P+A276S+H358D+A364G+S388K;
[5301] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+Q496E;
[5302] A25W+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K;
[5303] V45L+A117S+L149R+N168G+S214Q+V258P+A276S+H358D+A364G+S388K;
[5304] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S389H;
[5305] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+T480L;
[5306] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+Q385C+S388K;
[5307] V45L+S92D+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K;
[5308] V45L+A117S+L149R+A170S+S214Q+V258P+A276S+H358D+A364G+S388K;
[5309] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+Y391V;
[5310] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+T480N;
[5311] D9E+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K;
[5312] V45L+A117S+L149R+S214Q+H219I+V258P+A276S+H358D+A364G+S388K;
[5313] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+A499L;
[5314] V45L+A117S+L149R+S214Q+T215V+V258P+A276S+H358D+A364G+S388K;
[5315] V45L+A117S+L149R+S214Q+H219V+V258P+A276S+H358D+A364G+S388K;
[5316] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S389V;
[5317] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+V393H;
[5318] V45L+A117S+N127D+L149R+S214Q+V258P+A276S+H358D+A364G+S388K;
[5319] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+A472L;
[5320] V45L+A117S+L149R+T211H+S214Q+V258P+A276S+H358D+A364G+S388K;
[5321] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+T480L;
[5322] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+V393R;
[5323] V45L+A117S+L149R+S214Q+V258P+A276S+A286S+H358D+A364G+S388K;
[5324] V45L+A117S+L149R+S214Q+V258P+A276S+N355G+H358D+A364G+S388K;
[5325] V45L+A117S+L149R+S214Q+V258P+A276S+N355G+A364G+S388K+D470T;
[5326] V45L+A117S+L149R+S214Q+V258P+A276S+A286E+H358D+A364G+S388K;
[5327] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+Y386G+S388K;
[5328] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+S501E;
[5329] V45L+A79C+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V;
[5330] V45L+A79C+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[5331] V45L+A117S+L149R+S214E+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[5332] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[5333] V45L+A117S+L149R+S214E+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[5334] V45L+A117S+L149R+S214Q+V258P+A276Q+H358D+A364G+S388K+D470T+R483V;
[5335] V45L+A117S+L149R+S214Q+V258P+A276Q+H358D+A364G+S388K+D470T+L530R;
[5336] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[5337] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470A+R483V;
[5338] V45N+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[5339] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388H+D470T+L530R;
[5340] V45N+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[5341] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388A+D470T+L530R;
[5342] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388A+D470T+R483V;
[5343] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388L+D470T+R483V;
[5344] V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[5345] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+G394A+D470T+R483V;
[5346] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L478N;
[5347] V45L+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+D470T;
[5348] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+T366I+S388K+D470T;
[5349] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S473G;
[5350] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L478P;
[5351] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394D+D470T;
[5352] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+Q384A+S388K+D470T+R483V;
[5353] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N529T;
[5354] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394Q+D470T;
[5355] V45L+A117S+L149R+G187L+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[5356] V45L+A117S+L149R+S214Q+V258P+A276S+Q314A+H358D+A364G+S388K+D470T;
[5357] V45L+A117S+L149R+S214Q+V258P+A276S+V350L+H358D+A364G+S388K+D470T;
[5358] V45L+A117S+L149R+G187K+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[5359] V45L+A117S+L149R+S214Q+W250Y+V258P+A276S+H358D+A364G+S388K+D470T;
[5360] V45L+A117S+L149R+S214Q+V258P+A276S+A286E+H358D+A364G+S388K+D470T;
[5361] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+Q384A+S388K+D470T;
[5362] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S528H;
[5363] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+Q496R;
[5364] V45L+A117S+L149R+N163H+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[5365] V45L+A117S+L149R+S214Q+V258P+A276S+S282N+H358D+A364G+S388K+D470T;
[5366] D11E+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[5367] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+T366V+S388K+D470T;
[5368] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S473K;
[5369] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388R+D470T+R483V;
[5370] V45L+A117S+L149R+S214Q+V258P+A276S+Q314A+A364G+S388K+D470T+R483V;
[5371] V45L+S92D+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[5372] V45L+A117S+L149R+S214Q+V258P+N260H+A276S+H358D+A364G+S388K+D470T;
[5373] V45L+A117S+L149R+G187S+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[5374] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T477K;
[5375] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N474G;
[5376] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+N395D+D470T;
[5377] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S501N;
[5378] V45L+A117S+N127D+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[5379] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+V393R+D470T;
[5380] V45L+A117S+L149R+S173Y+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[5381] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T480N;
[5382] V45L+A117S+L149R+N168G+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[5383] V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V;
[5384] V45L+D113T+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[5385] V45 L+A117S+L149R+S214Q+V258P+A276S+A364G+T366V+S388K+D470T+R483V;
[5386] V45L+A117S+L149R+S214Q+V258P+A276S+H358T+A364G+S388K+D470T+R483V;
[5387] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+V393R+D470T+R483V;
[5388] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+Q496Q;
[5389] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+G394Q+D470T+R483V;
[5390] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+T366I+S388K+D470T+R483V;
[5391] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L484S;
[5392] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+A499L;
[5393] V45L+A117S+L149R+S214Q+V258P+A276S+H358T+A364G+S388K+D470T+L530R;
[5394] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+V498I;
[5395] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V;
[5396] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+N476D+R483V;
[5397] D9E+V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V;
[5398] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S501E;
[5399] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S481A;
[5400] V45L+A117S+L149R+S214Q+H219V+V258P+A276S+H358D+A364G+S388K+D470T;
[5401] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S481S;
[5402] V45L+A117S+L149R+G187K+S214Q+V258P+A276S+A364G+S388K+D470T+R483V;
[5403] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+N395D+D470T+R483V;
[5404] V45L+A117S+L149R+G187L+S214Q+V258P+A276S+A364G+S388K+D470T+R483V;
[5405] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+V497P;
[5406] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N527H;
[5407] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+Q496Q;
[5408] V45L+A117S+L149R+N168G+S214Q+V258P+A276S+A364G+S388K+D470T+R483V;
[5409] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+N476N+R483V;
[5410] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+T477V+R483V;
[5411] V45L+A117S+L149R+S214Q+V258P+A276S+V350L+A364G+S388K+D470T+R483V;
[5412] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+L478N+R483V;
[5413] M28P+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[5414] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+V393H+D470T+R483V;
[5415] V45L+Q61R+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V;
[5416] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+V497P;
[5417] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+V498I;
[5418] V45L+A117S+L149R+S214Q+V258P+A276S+A286E+A364G+S388K+D470T+R483V;
[5419] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+T477K+R483V;
[5420] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+Q496E;
[5421] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+Q496R;
[5422] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+A499L;
[5423] V45L+A117S+L149R+S214Q+T215I+V258P+A276S+H358D+A364G+S388K+D470T;
[5424] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+Y391V+D470T+R483V;
[5425] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N476D;
[5426] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+V393H+D470T;
[5427] V45L+A117S+L149R+S214Q+V258P+A276S+A286S+A364G+S388K+D470T+R483V;
[5428] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+S501E;
[5429] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+N529T;
[5430] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+S501N;
[5431] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+S481S+R483V;
[5432] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+L478P+R483V;
[5433] D11E+V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V;
[5434] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T477V;
[5435] V45L+A117S+L149R+T211H+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[5436] V45L+A117S+L149R+S214Y+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[5437] V45L+A117S+L149R+S214Q+W250Y+V258P+A276S+A364G+S388K+D470T+R483V;
[5438] V45L+S92D+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V;
[5439] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+N527H;
[5440] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+Q385C+S388K+D470T;
[5441] V45L+A117S+L149R+S173Y+S214Q+V258P+A276S+A364G+S388K+D470T+R483V;
[5442] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+S389H+D470T+R483V;
[5443] V45L+A117S+L149R+S214Q+H219V+V258P+A276S+A364G+S388K+D470T+R483V;
[5444] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+Q496E;
[5445] V45L+A117S+L149R+A170S+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[5446] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S389V+D470T;
[5447] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[5448] V45L+A117S+L149R+S214Q+H219I+V258P+A276S+A364G+S388K+D470T+R483V;
[5449] V45 L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+A499Y;
[5450] V45L+A117S+L149R+S214Q+V258P+A276S+L281V+A364G+S388K+D470T+R483V;
[5451] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+V500T;
[5452] V45L+A117S+L149R+T180Q+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[5453] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+V500V;
[5454] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+G526T;
[5455] V45L+A117S+L149R+S214Q+V258P+A276S+A286S+H358D+A364G+S388K+D470T;
[5456] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470A+L530R;
[5457] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+D525L;
[5458] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N476N;
[5459] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S389H+D470T;
[5460] V45L+A117S+L149R+S214Y+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[5461] A25W+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[5462] V45L+A117S+L149R+S214Q+T215V+V258P+A276S+A364G+S388K+D470T+R483V;
[5463] V45L+Q61R+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[5464] V45L+A117S+L149R+S214Q+H219I+V258P+A276S+H358D+A364G+S388K+D470T;
[5465] V45L+A117S+L149R+T211H+S214Q+V258P+A276S+A364G+S388K+D470T+R483V;
[5466] V45L+D95N+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S473G;
[5467] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+G503L;
[5468] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+D525L;
[5469] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+V500T;
[5470] V45L+A117S+L149R+S214Q+T215V+V258P+A276S+H358D+A364G+S388K+D470T;
[5471] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T480L;
[5472] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+S389V+D470T+R483V;
[5473] V45 L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+V497E;
[5474] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470V+R483V;
[5475] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470K+R483V;
[5476] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+A472L;
[5477] V45L+D113T+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V;
[5478] V45L+A117S+L149R+S214Q+T215K+V258P+A276S+A364G+S388K+D470T+R483V;
[5479] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+V497W;
[5480] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+W495E;
[5481] V45L+A117S+L149R+S214Q+T215K+V258P+A276S+H358D+A364G+S388K+D470T;
[5482] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388H+D470T+R483V;
[5483] V45L+A117S+L149R+S214Q+V258P+A276S+N355G+H358D+A364G+S388K+D470T;
[5484] V45L+A79C+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L 530R;
[5485] V45L+A79C+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R 483V;
[5486] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+Q385C+S388K+D470T+R483V;
[5487] V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R 483V;
[5488] V45L+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+D470T+R483V;
[5489] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+T366I+S388K+D470T+R 483V;
[5490] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+Q384A+S388K+D470T+L530R;
[5491] V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L 530R;
[5492] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R 483V;
[5493] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+V393H+D470T+R483V;
[5494] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394A+D470T+R483V;
[5495] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+V393H+D470T+L530R;
[5496] V45L+A117S+L149R+S214Q+V258P+A276S+A286E+H358D+A364G+S388K+D470T+R483V;
[5497] D11E+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R 483V;
[5498] V45L+A117S+L149R+G187L+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[5499] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+Q384A+S388K+D470T+V45L+A117S+L149R+G187K+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[5500] V45L+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+D470T+L530R;
[5501] V45L+A117S+L149R+G187L+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[5502] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394Q+D470T+R483V;
[5503] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394A+D470T+L530R;
[5504] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+T366V+S388K+D470T+L530R;
[5505] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394Q+D470T+L530R;
[5506] V45L+A117S+L149R+S214Q+V258P+A276S+S282N+H358D+A364G+S388K+D470T+R483V;
[5507] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+N395D+D470T+R483V;
[5508] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N476D+R483V;
[5509] V45L+A117S+L149R+S214Q+V258P+A276S+V350L+H358D+A364G+S388K+D470T+R483V;
[5510] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T477K+R483V;
[5511] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+Q496R;
[5512] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+W495E;
[5513] V45L+A117S+L149R+S214Q+V258P+A276S+A286E+H358D+A364G+S388K+D470T+L530R;
[5514] V45L+A117S+L149R+G187K+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[5515] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+Y391V+D470T+R483V;
[5516] D9E+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L5 30R;
[5517] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T477V+R483V;
[5518] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N476N+R483V;
[5519] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+V393R+D470T+R483V;
[5520] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T480L+L530R;
[5521] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S481A+L530R;
[5522] V45L+A117S+L149R+S214Q+W250Y+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[5523] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S481S+R483V;
[5524] V45L+A117S+L149R+S173Y+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[5525] V45L+A117S+L149R+T180Q+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[5526] D11E+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L 530R;
[5527] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N476D+L530R;
[5528] V45L+A117S+L149R+S214Q+V258P+A276S+A286S+H358D+A364G+S388K+D470T+R483V;
[5529] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+Q496Q;
[5530] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+Q496E;
[5531] V45L+Q61R+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L 530R;
[5532] V45L+A117S+L149R+S214Q+V258P+A276S+Q314A+H358D+A364G+S388K+D470T+L530R;
[5533] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L478P+R483V;
[5534] A25W+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+V45L+A117S+L149R+T180Q+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[5535] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+L484K;
[5536] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N474G+L530R;
[5537] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+N395D+D470T+L530R;
[5538] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+T366V+S388K+D470T+R483V;
[5539] V45L+A117S+L149R+N168G+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[5540] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+L484S;
[5541] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+L484 D;
[5542] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+S528H;
[5543] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+S501N;
[5544] V45L+A117S+L149R+S173Y+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[5545] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+A499L;
[5546] V45L+S92D+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R 483V;
[5547] V45L+A117S+L149R+S214Q+V258P+A276S+Q314A+H358D+A364G+S388K+D470T+R483V;
[5548] V45L+A117S+L149R+S214Q+V258P+A276S+N355G+H358D+A364G+S388K+D470T+L530R;
[5549] V45L+A117S+L149R+S214Q+V258P+A276S+V350L+H358D+A364G+S388K+D470T+L530R;
[5550] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S481S+L530R;
[5551] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+Q496E+L530R;
[5552] V45L+A117S+L149R+N168G+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[5553] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+V498I+L 530R;
[5554] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+A499Y;
[5555] V45L+A117S+L149R+S214Q+V258P+A276S+A286S+H358D+A364G+S388K+D470T+L530R;
[5556] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S501N+L530R;
[5557] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N476N+L530R;
[5558] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T477V+L530R;
[5559] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L478N+L530R;
[5560] V45L+S92D+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L 530R;
[5561] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+V500V+L530R;
[5562] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+V500V;
[5563] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L478P+L530R;
[5564] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+S501E;
[5565] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+D525L+L530R;
[5566] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+G526T+L530R;
[5567] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N527H+L530R;
[5568] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T477K+L530R;
[5569] M28P+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L 530R;
[5570] D9E+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R4 83V;
[5571] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S501E+L530R;
[5572] V45L+A117S+L149R+S214Q+W250Y+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[5573] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+A499L+L530R;
[5574] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+A472I+L 530R;
[5575] V45L+A117S+N127D+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[5576] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+V500T+L530R;
[5577] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+N527H;
[5578] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T480N+L530R;
[5579] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+V497P;
[5580] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+V498I;
[5581] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T480N+R483V;
[5582] V45L+A117S+L149R+S214Q+H219V+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[5583] M28P+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[5584] V45L+A117S+L149R+A170S+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[5585] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S389H+D470T+L530R;
[5586] V45L+D113T+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[5587] V45L+A117S+L149R+N163H+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+V45L+A117S+L149R+T211H+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[5588] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+V500T;
[5589] V45L+D113T+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[5590] V45L+D95N+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394A+D470T;
[5591] V45L+A93T+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+A 499Y;
[5592] V45L+A117S+L149R+S214Q+T215I+V258P+A276S+H358D+A364G+S388K+D470T+R 483V;
[5593] V45L+A117S+L149R+S214Q+H219I+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[5594] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+Q385C+S388K+D470T+L530R;
[5595] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+L530R;
[5596] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+G503L;
[5597] V45L+A117S+L149R+S214Q+T215V+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[5598] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S481A+R483V;
[5599] V45L+A117S+L149R+S214Q+T215V+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[5600] V45L+A117S+L149R+G187S+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[5601] V45L+A117S+L149R+T211H+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[5602] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+G526T;
[5603] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+D525L;
[5604] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S528H+L530R;
[5605] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+I469T+D470T+R 483V;
[5606] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N529T+L530R;
[5607] V45L+A117S+L149R+S214Q+V258P+A276S+S282N+H358D+A364G+S388K+D470T+L530R;
[5608] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+G503L+L530R;
[5609] V45L+A117S+L149R+S214Q+H219I+V258P+A276S+H358D+A364G+S388K+D470T+L 530R;
[5610] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+V497P+L530R;
[5611] V45L+A117S+L149R+S214Q+T215I+V258P+A276S+H358D+A364G+S388K+D470T+L 530R;
[5612] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S389V+D470T+R483V;
[5613] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S389V+D470T+L530R;
[5614] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+V497D;
[5615] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L478N+R483V;
[5616] V45L+T70R+D95N+A117S+L149R+S214Q+V258P+A276S+L356M+H358D+A364G+S3 88K;
[5617] V45L+A117S+L149R+S214Q+T215K+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[5618] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+V497W;
[5619] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L 530R;
[5620] V45L+A117S+L149R+S214Q+T215K+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[5621] V45L+Q61R+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[5622] V45L+A117S+L149R+S214Q+V258P+A276S+N355G+H358D+A364G+S388K+D470T+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+V497E;
[5623] V45L+A117S+L149R+N163H+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[5624] V45 L+A117S+L149R+S214Q+V258P+A276S+H358 D+A364G+Y386G+S388K+D470T+R483V;
[5625] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394D+D470T+R483V;
[5626] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G 394A+D470T+R483V;
[5627] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G 394A+D470T+R483V;
[5628] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G 394A+D470T+R483V;
[5629] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G 394A+D470T+R483V;
[5630] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G 394A+D470T+R483V;
[5631] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G 394A+D470T+R483V;
[5632] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G 394A+D470T+R483V;
[5633] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G 394A+D470T+R483V;
[5634] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G 394A+D470T+R483V;
[5635] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G 394A+D470T+R483V;
[5636] V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G 394A+D470T+L530R;
[5637] V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+D 470T+R483V+L530R;
[5638] V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+D 470T+R483V+L530R;
[5639] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G 394A+D470T+R483V;
[5640] V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G 394A+D470T+R483V+L530R;
[5641] V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G 394A+D470T+R483V+L530R;
[5642] V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G 394A+D470T+R483V+L530R;
[5643] V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G 394A+D470T+R483V+L530R;
[5644] V45L+A117S+L149R+G187K+S214Q+V258P+A276S+A286E+H358D+A364G+Q384A+S388K+V393H+D470T+R483V;
[5645] V45L+A117S+L149R+G187K+S214Q+V258P+A276S+A286E+H358D+A364G+Q384A+S388K+N395D+D470T+R483V;
[5646] V45L+A117S+L149R+G187K+S214E+T215I+V258P+A276S+A286E+H358D+A364G+S 388K+V393H+D470T+R483V;
[5647] V45L+A117S+L149R+G187K+S214E+T215I+V258P+A276S+A286E+H358D+A364G+S 388K+N395D+D470T+R483V;
[5648] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G 394A+C468V+D470T+R483V;
[5649] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G 394A+0468A+D470T+R483V;
[5650] V45L+T70R+A117S+L149R+S214Q+C243V+V258P+A276S+L281V+H358D+A364G+S 388K+G394A+D470T+R483V;
[5651] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G 394A+C468L+D470T+R483V;
[5652] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+C375V+S 388K+G394A+D470T+R483V;
[5653] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G 394A+C468S+D470T+R483V;
[5654] V45L+C60L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S3 88K+G394A+D470T+R483V;
[5655] V45L+C69L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S3 88K+G394A+D470T+R483V;
[5656] V45L+C60A+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S3 88K+G394A+D470T+R483V;
[5657] V45L+T70R+A117S+L149R+S214Q+C243L+V258P+A276S+L281V+H358D+A364G+S 388K+G394A+D470T+R483V;
[5658] V45L+C60S+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S3 88K+G394A+D470T+R483V;
[5659] V45L+C69A+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S3 88K+G394A+D470T+R483V;
[5660] V45L+T70R+A117S+L149R+C161S+S214Q+V258P+A276S+L281V+H358D+A364G+S 388K+G394A+D470T+R483V;
[5661] V45L+C69V+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S3 88K+G394A+D470T+R483V;
[5662] V45L+C60V+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S3 88K+G394A+D470T+R483V;
[5663] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+C375A+S 388K+G394A+D470T+R483V;
[5664] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+C375S+S 388K+G394A+D470T+R483V;
[5665] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G 394A+D470T+R483V+C540A;
[5666] V45L+C69S+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S3 88K+G394A+D470T+R483V;
[5667] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+C375L+S 388K+G394A+D470T+R483V;
[5668] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G 394A+D470T+R483V+C540L;
[5669] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G 394A+D470T+R483V+C522S;
[5670] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G 394A+D470T+R483V+C540S;
[5671] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G 394A+C396S+D470T+R483V;
[5672] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G 394A+0396A+D470T+R483V;
[5673] C40L+V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S3 88K+G394A+D470T+R483V;
[5674] C40A+V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S3 88K+G394A+D470T+R483V;
[5675] C40S+V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S3 88K+G394A+D470T+R483V;
[5676] C40V+V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S3 88K+G394A+D470T+R483V;
[5677] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G 394A+C396V+D470T+R483V;
[5678] V45L+T70R+A117S+L149R+C161V+S214Q+V258P+A276S+L281V+H358D+A364G+S 388K+G394A+D470T+R483V;
[5679] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G 394A+C396L+D470T+R483V;
[5680] V45L+T70R+A117S+L149R+C161L+S214Q+V258P+A276S+L281V+H358D+A364G+S 388K+G394A+D470T+R483V;
[5681] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G 394A+D470T+R483V+C522A;
[5682] V45L+T70R+A117S+L149R+S214Q+C243S+V258P+A276S+L281V+H358D+A364G+S 388K+G394A+D470T+R483V;
[5683] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G 394A+D470T+R483V+C522V;
[5684] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G 394A+D470T+R483V+C540V;
[5685] V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q3 84A+S388K+G394Q+D470T+R483V;
[5686] V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q3 84A+S388K+G394A+D470T+R483V;
[5687] V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q3 84A+S388K+V393H+D470T+R483V;
[5688] V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q3 84A+S388K+V393H+D470T+R483V;
[5689] V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q3 84A+S388K+G394A+D470T+R483V;
[5690] V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q3 84A+S388K+V393H+D470T+R483V;
[5691] V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q3 84A+S388K+G394A+D470T+R483V;
[5692] V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q3 84A+S388K+V393H+D470T+R483V;
[5693] V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q3 84A+S388K+G394A+D470T+R483V;
[5694] V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+A286E+H358D+A3 64G+Q384A+S388K+V393H+D470T+R483V; or V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+A286E+H358D+A3 64G+Q384A+S388K+V393H+D470T+R483V.
[5695] Paragraph 8. The xylanase variant according to any one of the preceding paragraphs, wherein the variant comprises at least one of the following substitutions or combinations of substitutions:
[5696] V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+A286E+H358D+A364G+Q384A+S388K+V393H+D470T+R483V;
[5697] V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q384A+S388K+G394Q+D470T+R483V;
[5698] V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q384A+S388K+G394A+D470T+R483V;
[5699] V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q384A+S388K+V393H+D470T+R483V;
[5700] V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q384A+S388K+V393H+D470T+R483V;
[5701] V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q384A+S388K+G394A+D470T+R483V;
[5702] V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q384A+S388K+V393H+D470T+R483V;
[5703] V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q384A+S388K+G394A+D470T+R483V;
[5704] V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+A286E+H358D+A364G+Q384A+S388K+V393H+D470T+R483V;
[5705] V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q384A+S388K+V393H+D470T+R483V;
[5706] V45L+Q61K+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+Q384A+S388K+G394A+D470T+R483V;
[5707] V45L+A79C+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[5708] V45L+A79C+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[5709] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[5710] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[5711] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[5712] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[5713] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[5714] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[5715] V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V+L530R;
[5716] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[5717] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[5718] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[5719] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[5720] V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+L530R;
[5721] V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V+L530R;
[5722] V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V+L530R;
[5723] V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+D470T+R483V+L530R;
[5724] V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V+L530R;
[5725] V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+D470T+R483V+L530R;
[5726] V45L+A117S+L149R+G187K+S214Q+V258P+A276S+A286E+H358D+A364G+Q384A+S388K+V393H+D470T+R483V;
[5727] V45L+A117S+L149R+G187K+S214Q+V258P+A276S+A286E+H358D+A364G+Q384A+S388K+N395D+D470T+R483V;
[5728] V45L+A117S+L149R+G187K+S214E+T215I+V258P+A276S+A286E+H358D+A364G+S388K+V393H+D470T+R483V;
[5729] V45L+A117S+L149R+G187K+S214E+T215I+V258P+A276S+A286E+H358D+A364G+S388K+N395D+D470T+R483V;
[5730] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+Q385C+S388K+D470T+R483V;
[5731] V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[5732] V45L+A79C+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V;
[5733] V45L+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+D470T+R483V;
[5734] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+T366I+S388K+D470T+R483V;
[5735] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[5736] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+Q384A+S388K+D470T+L530R;
[5737] V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[5738] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[5739] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+V393H+D470T+R483V;
[5740] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394A+D470T+R483V;
[5741] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+V393H+D470T+L530R;
[5742] V45L+A117S+L149R+S214Q+V258P+A276S+A286E+H358D+A364G+S388K+D470T+R483V;
[5743] D11E+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[5744] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+C468V+D470T+R483V;
[5745] V45L+A79C+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T V45L+A79C+L149R+S214E+V258P+A276S+A364G+S388K;
[5746] V45L+A117S+L149R+G187L+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[5747] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+Q384A+S388K+D470T+R483V;
[5748] V45L+A117S+L149R+G187K+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[5749] V45L+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+D470T+L530R;
[5750] V45L+A117S+L149R+S214E+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[5751] V45L+A117S+L149R+G187L+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[5752] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394Q+D470T+R483V;
[5753] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394A+D470T+L530R;
[5754] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+T366V+S388K+D470T+L530R;
[5755] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394Q+D470T+L530R;
[5756] V45L+A117S+L149R+S214Q+V258P+A276S+S282N+H358D+A364G+S388K+D470T+R483V;
[5757] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+N395D+D470T+R483V;
[5758] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N476D+R483V;
[5759] V45L+A117S+L149R+S214Q+V258P+A276S+V350L+H358D+A364G+S388K+D470T+R483V;
[5760] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T477K+R483V;
[5761] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+Q496R;
[5762] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+0468A+D470T+R483V;
[5763] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+W495E;
[5764] V45L+A117S+L149R+S214Q+V258P+A276S+A286E+H358D+A364G+S388K+D470T+L530R;
[5765] V45L+A117S+L149R+G187K+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[5766] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+Y391V+D470T+R483V;
[5767] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[5768] D9E+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[5769] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T477V+R483V;
[5770] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N476N+R483V;
[5771] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+V393R+D470T+R483V;
[5772] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T480L+L530R;
[5773] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S481A+L530R;
[5774] V45L+A117S+L149R+S214Q+W250Y+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[5775] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S481S+R483V;
[5776] V45L+A117S+L149R+S173Y+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[5777] V45L+T70R+A117S+L149R+S214Q+C243V+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[5778] V45L+A117S+L149R+T180Q+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[5779] D11E+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[5780] V45L+A117S+L149R+S214E+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[5781] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N476D+L530R;
[5782] V45L+A117S+L149R+S214Q+V258P+A276S+A286S+H358D+A364G+S388K+D470T+R483V;
[5783] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+Q496Q;
[5784] V45L+A117S+L149R+S214Q+V258P+A276Q+H358D+A364G+S388K+D470T+R483V;
[5785] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+Q496E;
[5786] V45L+Q61R+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[5787] V45L+A117S+L149R+S214Q+V258P+A276S+Q314A+H358D+A364G+S388K+D470T+L530R;
[5788] V45L+A117S+L149R+S214Q+V258P+A276Q+H358D+A364G+S388K+D470T+L530R;
[5789] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L478P+R483V;
[5790] A25W+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[5791] V45L+A117S+L149R+T180Q+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[5792] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+L484K V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N474G+L530R;
[5793] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+N395D+D470T+L530R;
[5794] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+T366V+S388K+D470T+R483V;
[5795] V45L+A117S+L149R+N168G+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[5796] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+L484S;
[5797] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[5798] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+L484D;
[5799] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+S528H;
[5800] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+S501N;
[5801] V45L+A117S+L149R+S173Y+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[5802] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+A499L;
[5803] V45L+S92D+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[5804] V45L+A117S+L149R+S214Q+V258P+A276S+Q314A+H358D+A364G+S388K+D470T+R483V;
[5805] V45L+A79C+L149R+S214Q+V258P+A276S+A364G+S388K;
[5806] V45L+A117S+L149R+S214Q+V258P+A276S+N355G+H358D+A364G+S388K+D470T+L530R;
[5807] V45L+A117S+L149R+S214Q+V258P+A276S+V350L+H358D+A364G+S388K+D470T+L530R;
[5808] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S481S+L530R;
[5809] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+Q496E+L530R;
[5810] V45L+A117S+L149R+N168G+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[5811] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+V498I+L530R;
[5812] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470A+R483V;
[5813] V45N+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[5814] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+A499Y;
[5815] V45L+A79C+L149R+V258P+A276S+Q314A+A364G+S388K;
[5816] V45L+A79C+L149R+V258P+A276S+L281V+A364G+S388K;
[5817] V45L+A117S+L149R+S214Q+V258P+A276S+A286S+H358D+A364G+S388K+D470T+L530R;
[5818] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S501N+L530R;
[5819] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N476N+L530R;
[5820] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T477V+L530R;
[5821] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388H+D470T+L530R;
[5822] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L478N+L530R;
[5823] V45L+S92D+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[5824] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+V500V+L530R;
[5825] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+V500V;
[5826] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L478P+L530R;
[5827] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+S501E;
[5828] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+D525L+L530R;
[5829] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+G526T+L530R;
[5830] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N527H+L530R;
[5831] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T477K+L530R;
[5832] M28P+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[5833] D9E+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[5834] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S501E+L530R;
[5835] V45L+A117S+L149R+S214Q+W250Y+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[5836] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+A499L+L530R;
[5837] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+A472I+L530R;
[5838] V45L+A117S+N127D+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[5839] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+V500T+L530R;
[5840] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+N527H;
[5841] V45N+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[5842] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T480N+L530R;
[5843] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+V497P;
[5844] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+V498I;
[5845] V45L+A79C+L149R+S173Y+V258P+A276S+A364G+S388K;
[5846] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T480N+R483V;
[5847] V45L+A117S+L149R+S214Q+H219V+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[5848] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388A+D470T+L530R;
[5849] M28P+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[5850] V45L+A117S+L149R+A170S+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[5851] V45L+A79C+L149R+G187K+V258P+A276S+A364G+S388K;
[5852] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S389H+D470T+L530R;
[5853] V45L+D113T+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[5854] V45L+A117S+L149R+N163H+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[5855] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388A+D470T+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388L+D470T+R483V;
[5856] V45L+Q61R+A79C+L149R+V258P+A276S+A364G+S388K;
[5857] V45L+A79C+L149R+N168G+V258P+A276S+A364G+S388K;
[5858] V45L+A117S+L149R+T211H+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[5859] V45L+A79C+L149R+T215V+V258P+A276S+A364G+S388K;
[5860] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+V500T;
[5861] V45L+A79C+L149R+V258P+A276S+A286S+A364G+S388K;
[5862] V45L+A79C+L149R+H219V+V258P+A276S+A364G+S388K;
[5863] V45L+A79C+L149R+A170S+V258P+A276S+A364G+S388K;
[5864] V45L+D113T+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[5865] V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[5866] V45L+D95N+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394A+D470T;
[5867] V45L+A79C+L149R+V258P+A276S+A364G+S388K;
[5868] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+G394A+D470T+R483V;
[5869] V45L+A93T+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+A499Y;
[5870] V45L+A117S+L149R+S214Q+T215I+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[5871] V45L+A117S+L149R+S214Q+H219I+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[5872] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L478N;
[5873] V45L+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+D470T;
[5874] V45L+A117S+L149R+S214E+V258P+A276S+H358D+A364G+S388K+D470T;
[5875] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+C468L+D470T+R483V;
[5876] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+Q385C+S388K+D470T+L530R;
[5877] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+T366I+S388K+D470T;
[5878] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S473G;
[5879] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L478P;
[5880] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394D+D470T;
[5881] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+Q384A+S388K+D470T+R483V;
[5882] D11E+V45L+A79C+L149R+V258P+A276S+A364G+S388K;
[5883] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+L530R;
[5884] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N529T;
[5885] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394Q+D470T;
[5886] V45L+A117S+L149R+G187L+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[5887] V45L+A79C+L149R+V258P+A276S+A286E+A364G+S388K;
[5888] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+G503L;
[5889] V45L+A117S+L149R+S214Q+V258P+A276S+Q314A+H358D+A364G+S388K+D470T;
[5890] V45L+A117S+L149R+S214Q+V258P+A276S+V350L+H358D+A364G+S388K+D470T;
[5891] V45L+A117S+L149R+G187K+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[5892] V45L+A117S+L149R+S214Q+W250Y+V258P+A276S+H358D+A364G+S388K+D470T;
[5893] V45L+A117S+L149R+S214Q+V258P+A276S+A286E+H358D+A364G+S388K+D470T;
[5894] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+Q384A+S388K+D470T;
[5895] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388R+D470T;
[5896] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S528H;
[5897] V45L+A117S+L149R+S214Q+T215V+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[5898] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+Q496R;
[5899] V45L+A117S+L149R+N163H+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[5900] V45L+A117S+L149R+S214Q+V258P+A276S+S282N+H358D+A364G+S388K+D470T;
[5901] V45L+A117S+L149R+S214Q+V258P+A276Q+H358D+A364G+S388K+D470T;
[5902] D11E+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[5903] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+T366V+S388K+D470T;
[5904] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S473K;
[5905] V45L+A79C+L149R+T180Q+V258P+A276S+A364G+S388K;
[5906] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S481A+R483V;
[5907] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388R+D470T+R483V;
[5908] V45L+A117S+L149R+S214Q+V258P+A276S+Q314A+A364G+S388K+D470T+R483V;
[5909] V45L+S92D+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[5910] V45L+A117S+L149R+S214Q+V258P+N260H+A276S+H358D+A364G+S388K+D470T;
[5911] V45L+A117S+L149R+G187S+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[5912] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T477K;
[5913] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N474G;
[5914] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+N395D+D470T;
[5915] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S501N;
[5916] V45L+A117S+N127D+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[5917] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+V393R+D470T;
[5918] V45L+A117S+L149R+S173Y+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[5919] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388H+D470T;
[5920] V45L+A117S+L149R+S214Q+T215V+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[5921] V45L+A117S+L149R+G187S+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[5922] V45L+A117S+L149R+T211H+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[5923] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T480N;
[5924] V45L+A117S+L149R+N168G+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[5925] V45L+A79C+L149R+H219I+V258P+A276S+A364G+S388K;
[5926] V45L+L149R+S214E+V258P+A276S+H358D+A364G+D470T;
[5927] V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V;
[5928] V45L+D113T+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[5929] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+T366V+S388K+D470T+R483V;
[5930] V45L+A117S+L149R+S214Q+V258P+A276S+H358T+A364G+S388K+D470T+R483V;
[5931] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+V393R+D470T+R483V;
[5932] V45N+A79C+L149R+V258P+A276S+A364G+S388K;
[5933] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+Q496Q;
[5934] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+G394Q+D470T+R483V;
[5935] V45L+A79C+L149R+V258P+A276S+V350L+A364G+S388K;
[5936] V45L+L149R+S214E+V258P+A276S+H358D+A364G+D470T;
[5937] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+T366I+S388K+D470T+R483V;
[5938] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+G526T;
[5939] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L484S;
[5940] V45L+A79C+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K;
[5941] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+A499L;
[5942] V45L+A117S+L149R+S214Q+V258P+A276S+H358T+A364G+S388K+D470T+L530R;
[5943] V45L+A79C+D113T+L149R+V258P+A276S+A364G+S388K;
[5944] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+D525L;
[5945] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+V498I;
[5946] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388L+D470T;
[5947] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V;
[5948] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S528H+L530R;
[5949] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+N476D+R483V;
[5950] D9E+V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V;
[5951] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S501E;
[5952] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S481A;
[5953] V45L+A117S+L149R+S214Q+H219V+V258P+A276S+H358D+A364G+S388K+D470T;
[5954] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+S481S;
[5955] V45L+A117S+L149R+G187K+S214Q+V258P+A276S+A364G+S388K+D470T+R483V;
[5956] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+N395D+D470T+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+I469T+D470T+R483V;
[5957] V45L+A79C+N127D+L149R+V258P+A276S+A364G+S388K;
[5958] D9E+V45L+A79C+L149R+V258P+A276S+A364G+S388K;
[5959] V45L+L149R+S214E+V258P+A276S+H358D+A364G+D470T;
[5960] V45L+A117S+L149R+G187L+S214Q+V258P+A276S+A364G+S388K+D470T+R483V;
[5961] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N529T+L530R;
[5962] V45L+A79C+L149R+W250Y+V258P+A276S+A364G+S388K;
[5963] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+V497P;
[5964] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N527H;
[5965] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+Q496Q;
[5966] V45L+A117S+L149R+N168G+S214Q+V258P+A276S+A364G+S388K+D470T+R483V;
[5967] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+N476N+R483V;
[5968] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+T477V+R483V;
[5969] V45L+A117S+L149R+S214Q+V258P+A276S+V350L+A364G+S388K+D470T+R483V;
[5970] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+L478N+R483V;
[5971] V45L+A117S+L149R+S214E+V258P+A276S+A364G+S388K+D470T+R483V;
[5972] M28P+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[5973] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+V393H+D470T+R483V;
[5974] V45L+Q61R+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V;
[5975] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+V497P;
[5976] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+V498I;
[5977] V45L+A117S+L149R+S214Q+V258P+A276S+S282N+H358D+A364G+S388K+D470T+L530R;
[5978] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+C375V+S388K+G394A+D470T+R483V;
[5979] V45L+A117S+L149R+S214Q+V258P+A276S+A286E+A364G+S388K+D470T+R483V;
[5980] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388R+D470T+R483V;
[5981] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470A+R483V;
[5982] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+T477K+R483V;
[5983] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+Q496E;
[5984] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+Q496R;
[5985] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+A499L;
[5986] V45L+L149R+S214E+V258P+A276S+H358D+A364G+D470T;
[5987] V45L+L149R+S214E+V258P+A276S+H358D+A364G+D470T;
[5988] V45L+A117S+L149R+S214Q+T215I+V258P+A276S+H358D+A364G+S388K+D470T;
[5989] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+C468S+D470T+R483V;
[5990] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+Y391V+D470T+R483V;
[5991] V45L+A117S+L149R+S214Q+V258P+A276Q+A364G+S388K+D470T+R483V;
[5992] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+G503L+L530R;
[5993] V45L+A117S+L149R+S214Q+H219I+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[5994] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N476D;
[5995] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+V393H+D470T;
[5996] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V;
[5997] V45L+A117S+L149R+S214Q+V258P+A276S+A286S+A364G+S388K+D470T+V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+S501E;
[5998] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+N529T;
[5999] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+S501N, V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[6000] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+S481S+R483V;
[6001] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+L478P+R483V;
[6002] D11E+V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V;
[6003] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T477V;
[6004] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+V497P+L530R;
[6005] V45L+A117S+L149R+T211H+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[6006] V45L+A117S+L149R+S214Y+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[6007] V45L+A117S+L149R+S214Q+W250Y+V258P+A276S+A364G+S388K+D470T+R483V;
[6008] V45L+S92D+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V;
[6009] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+N527H;
[6010] V45N+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V;
[6011] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+Q385C+S388K+D470T;
[6012] V45L+A117S+L149R+S173Y+S214Q+V258P+A276S+A364G+S388K+D470T+R483V;
[6013] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388H+D470T+R483V;
[6014] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+S389H+D470T+R483V;
[6015] V45L+A117S+L149R+S214Q+H219V+V258P+A276S+A364G+S388K+D470T+V45L+A79C+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T;
[6016] V45L+A117S+L149R+S214Q+T215I+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[6017] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+Q496E;
[6018] V45L+A117S+L149R+A170S+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[6019] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S389V+D470T+R483V;
[6020] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S389V+D470T+L530R;
[6021] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388A+D470T;
[6022] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S389V+D470T;
[6023] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[6024] V45L+A117S+L149R+S214Q+H219I+V258P+A276S+A364G+S388K+D470T+R483V;
[6025] V45L+A79C+L149R+N163H+V258P+A276S+A364G+S388K;
[6026] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+A499Y;
[6027] V45L+A117S+L149R+S214Q+V258P+A276S+L281V+A364G+S388K+D470T+R483V;
[6028] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+V500T;
[6029] V45L+A117S+L149R+T180Q+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[6030] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+V500V;
[6031] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+G526T;
[6032] V45L+C60L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[6033] V45L+C69L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[6034] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388A+D470T+R483V;
[6035] V45L+A117S+L149R+S214Q+V258P+A276S+A286S+H358D+A364G+S388K+D470T;
[6036] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+V497D;
[6037] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470A+L530R;
[6038] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+D525L;
[6039] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+N476N;
[6040] V45L+A117S+L149R+S214Q+V258P+A276S+L281V+A364G+S388K+D470T;
[6041] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+Q384A+S388K+D470T;
[6042] V45L+A117S+L149R+S214Q+V258P+A276S+A286E+A364G+S388K+D470T;
[6043] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+T477K;
[6044] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S389H+D470T;
[6045] V45L+A117S+L149R+S214Y+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[6046] V45L+A117S+L149R+S214Y+V258P+A276S+H358D+A364G+S388K+D470T;
[6047] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+G394A+D470T;
[6048] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+N476D;
[6049] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L478N+R483V;
[6050] V45L+C60A+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[6051] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+V393H+D470T;
[6052] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+N395D+D470T;
[6053] A25W+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[6054] V45L+T70R+A117S+L149R+S214Q+C243L+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[6055] V45L+A117S+L149R+S214Q+V258P+A276S+H358T+A364G+S388K+D470T;
[6056] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+L478N;
[6057] V45L+C60S+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[6058] V45L+A117S+L149R+S214Q+W250Y+V258P+A276S+A364G+S388K+D470T;
[6059] V45L+A117S+L149R+S214Q+T215V+V258P+A276S+A364G+S388K+D470T+R483V;
[6060] V45L+Q61R+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[6061] V45L+A117S+L149R+G187L+S214Q+V258P+A276S+A364G+S388K+D470T;
[6062] D9E+V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T;
[6063] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G;
[6064] V45L+C69A+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[6065] V45L+T70R+A117S+L149R+C161S+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[6066] V45L+A117S+L149R+S214Q+H219I+V258P+A276S+H358D+A364G+S388K+D470T;
[6067] V45L+A117S+L149R+S214Q+V258P+A276S+S282N+A364G+S388K+D470T;
[6068] V45L+A117S+L149R+T211H+S214Q+V258P+A276S+A364G+S388K+D470T+R483V;
[6069] V45L+D95N+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S473G;
[6070] V45L+T70R+D95N+A117S+L149R+S214Q+V258P+A276S+L356M+H358D+A364G+S388K;
[6071] D11E+V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T;
[6072] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+N476N;
[6073] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+G394D+D470T;
[6074] V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T;
[6075] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+G503L;
[6076] V45L+A117S+L149R+S214Q+V258P+A276S+A286S+A364G+S388K+D470T;
[6077] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470A;
[6078] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+G394Q+D470T;
[6079] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388R+D470T;
[6080] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+L478P;
[6081] V45L+A117S+L149R+S214Q+V258P+A276S+V350L+A364G+S388K+D470T;
[6082] V45L+D113T+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T;
[6083] V45L+A117S+L149R+T180Q+S214Q+V258P+A276S+A364G+S388K+D470T;
[6084] V45L+C69V+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[6085] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+D525L;
[6086] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T;
[6087] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+V500T;
[6088] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+S389H+D470T;
[6089] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+V393R+D470T;
[6090] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+Q496R;
[6091] V45L+A117S+N127D+L149R+S214Q+V258P+A276S+A364G+S388K+D470T;
[6092] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+A499Y;
[6093] V45L+A117S+L149R+S214Q+T215V+V258P+A276S+H358D+A364G+S388K+D470T;
[6094] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+T480L;
[6095] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388L+D470T;
[6096] V45L+A117S+L149R+S173Y+S214Q+V258P+A276S+A364G+S388K+D470T;
[6097] V45L+S92D+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T;
[6098] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+S389V+D470T+R483V;
[6099] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+N529T;
[6100] V45L+C60V+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[6101] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+V497E;
[6102] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+L478N;
[6103] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T;
[6104] M28P+V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T;
[6105] V45L+A117S+L149R+S214Q+V258P+A276Q+A364G+S388K+D470T;
[6106] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470V+R483V;
[6107] V45L+A117S+L149R+S214Y+V258P+A276S+A364G+S388K+D470T+R483V;
[6108] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+N395D;
[6109] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+T477K;
[6110] V45L+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K;
[6111] V45L+Q61R+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T;
[6112] V45L+A117S+L149R+S214Q+T215I+V258P+A276S+A364G+S388K+D470T;
[6113] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+Q496E;
[6114] V45L+A117S+L149R+G187K+S214Q+V258P+A276S+A364G+S388K+D470T;
[6115] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+W495I;
[6116] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+V498I;
[6117] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470K+R483V;
[6118] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+V500V;
[6119] D11E+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K;
[6120] V45L+A117S+L149R+A170S+S214Q+V258P+A276S+A364G+S388K+D470T;
[6121] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+Y391V+D470T;
[6122] V45L+A117S+L149R+S214Q+V258P+A276S+Q314A+A364G+S388K+D470T;
[6123] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+T477V;
[6124] A25W+V45L+A79C+L149R+S214E+V258P+A276S+A364G;
[6125] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394Q;
[6126] V45L+A117S+L149R+S214Q+H219V+V258P+A276S+A364G+S388K+D470T;
[6127] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+Q496Q;
[6128] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+C375A+S388K+G394A+D470T+R483V;
[6129] V45L+A117S+L149R+D192E+S214Q+V258P+A276S+H358D+A364G;
[6130] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+A472L;
[6131] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+A499Y;
[6132] V45L+A117S+L149R+S214Q+T215V+V258P+A276S+A364G+S388K+D470T;
[6133] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+Q385C+S388K+D470T;
[6134] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388A+D470T;
[6135] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388H+D470T;
[6136] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+T480N;
[6137] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+V497P;
[6138] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+A499L;
[6139] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+S501N;
[6140] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+D470T;
[6141] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+Q384A+S388K;
[6142] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+C375S+S388K+G394A+D470T+R483V;
[6143] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388L+D470T+R483V;
[6144] V45L+A79C+S92D+L149R+V258P+A276S+A364G+S388K;
[6145] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V+C540A;
[6146] V45N+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T;
[6147] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394A;
[6148] V45L+C69S+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[6149] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+V498I;
[6150] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G;
[6151] V45L+A117S+L149R+S214Q+H219I+V258P+A276S+A364G+S388K+D470T;
[6152] V45L+A117S+L149R+N163H+S214Q+V258P+A276S+A364G+S388K+D470T;
[6153] V45L+L149R+S214Q+V258P+A276S+H358D+A364G;
[6154] V45L+A117S+L149R+S214Q+V258P+A276S+Q314A+H358D+A364G+S388K;
[6155] V45L+A117S+L149R+S173Y+S214Q+V258P+A276S+H358D+A364G+S388K;
[6156] V45L+A117S+L149R+S214E+V258P+A276S+H358D+A364G+S388K;
[6157] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394D;
[6158] A25W+V45L+A79C+L149R+V258P+A276S+A364G;
[6159] V45L+L149R+S214Q+V258P+A276S+A286E+A364G+S388K;
[6160] V45L+Q61R+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K;
[6161] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+T366V+S388K;
[6162] V45L+A117S+L149R+D192E+S214Q+V258P+A276S+H358D+A364G;
[6163] V45L+A117S+L149R+T180Q+S214Q+V258P+A276S+H358D+A364G+S388K;
[6164] V45L+A117S+L149R+S214Q+T215I+V258P+A276S+H358D+A364G+S388K;
[6165] V45L+A117S+L149R+S214Q+W250Y+V258P+A276S+H358D+A364G+S388K;
[6166] V45L+L149R+S214Q+T215I+V258P+A276S+A364G+S388K;
[6167] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+N476D;
[6168] V45L+D113T+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V;
[6169] V45L+A117S+L149R+S214Q+T215K+V258P+A276S+A364G+S388K+D470T+R483V;
[6170] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K;
[6171] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+T477V;
[6172] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+L478P;
[6173] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S481A;
[6174] A25W+V45L+L149R+S214Q+V258P+A276S+A364G+S388K;
[6175] V45L+A117S+L149R+T211H+S214Q+V258P+A276S+A364G+S388K+D470T;
[6176] V45L+A117S+L149R+S214Q+T215K+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[6177] V45L+A79C+L149R+V258P+A276S+L281V+A364G;
[6178] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+R483V;
[6179] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+V500T;
[6180] V45L+A117S+L149R+S214Q+V258P+A276S+V350L+H358D+A364G+S388K;
[6181] V45L+A117S+L149R+G187K+S214Q+V258P+A276S+H358D+A364G+S388K;
[6182] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+C375L+S388K+G394A+D470T+R483V;
[6183] V45L+L149R+A170S+S214Q+V258P+A276S+A364G+S388K;
[6184] V45L+A117S+L149R+S214E+V258P+A276S+A364G+S388K+D470T;
[6185] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470V+R483V;
[6186] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+V500V;
[6187] V45L+Q61K+L149R+S214Q+V258P+A276S+A364G+S388K;
[6188] V45L+L149R+N168G+S214Q+V258P+A276S+A364G+S388K;
[6189] V45L+A117S+L149R+N163H+S214Q+V258P+A276S+H358D+A364G+S388K;
[6190] V45L+A79C+D95D+L149R+V258P+A276S+A364G+S388K;
[6191] V45L+Q77E+A79C+L149R+V258P+A276S+A364G+S388K;
[6192] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+V497W;
[6193] V45L+L149R+S214Q+V258P+A276S+S282N+A364G+S388K;
[6194] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388R;
[6195] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S481S;
[6196] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+V500T;
[6197] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V+C540L;
[6198] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V+C522S;
[6199] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+W495S;
[6200] V45L+L149R+S214Q+V258P+A276S+Q314A+A364G+S388K;
[6201] V45L+D113T+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K;
[6202] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+V497W;
[6203] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V+C540S;
[6204] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+C396S+D470T+R483V;
[6205] V45L+T70R+L149R+S214Q+V258P+A276S+A364G+S388K;
[6206] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+N474G;
[6207] V45L+A117S+L149R+S214Q+V258P+A276S+S282N+H358D+A364G+S388K;
[6208] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+Q496Q;
[6209] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+S389V+D470T;
[6210] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+C396A+D470T+R483V;
[6211] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S501E;
[6212] A25W+V45L+L149R+S214E+V258P+A276S+A364G;
[6213] V45L+L149R+S214Q+W250Y+V258P+A276S+A364G+S388K;
[6214] V45L+L149R+G187K+S214Q+V258P+A276S+A364G+S388K;
[6215] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+N476N;
[6216] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S473K;
[6217] V45L+A117S+L149R+G187L+S214Q+V258P+A276S+H358D+A364G+S388K;
[6218] C40L+V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[6219] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+Q496E;
[6220] A25W+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K;
[6221] V45L+L149R+V258P+A276S+L281V+H358T+A364G+S388K;
[6222] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388A;
[6223] V45L+A117S+L149R+N168G+S214Q+V258P+A276S+H358D+A364G+S388K;
[6224] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S389H;
[6225] M28P+V45L+L149R+S214Q+V258P+A276S+A364G+S388K;
[6226] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+T480L;
[6227] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+Q384A+S388K;
[6228] V45L+A93S+L149R+A252S+H334D;
[6229] C40A+V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[6230] V45L+L149R+G187L+S214Q+V258P+A276S+A364G+S388K;
[6231] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+Q385C+S388K;
[6232] V45L+L149R+S214Q+V258P+A276S+A286S+A364G+S388K;
[6233] V45L+S92D+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K;
[6234] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388L;
[6235] V45L+A117S+L149R+S214Q+V258P+A276S+A286E+A364G+S388K;
[6236] D9E+V45L+L149R+S214Q+V258P+A276S+A364G+S388K;
[6237] V45L+L149R+S173Y+S214Q+V258P+A276S+A364G+S388K;
[6238] V45L+A117S+L149R+A170S+S214Q+V258P+A276S+H358D+A364G+S388K;
[6239] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+Y391V;
[6240] V45L+A117S+L149R+S214Q+V258P+A276S+L281V+A364G+S388K;
[6241] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+G394D;
[6242] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+S473G;
[6243] V45L+A79C+L149R+V258P+A276S+H358T+A364G+S388K;
[6244] V45L+L149R+S214Q+V258P+A276Q+A364G+S388K;
[6245] A25W+V45L+L149R+S214E+V258P+A276S+H358T+A364G;
[6246] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+T480N;
[6247] D9E+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K;
[6248] V45L+A117S+L149R+S214Q+H219I+V258P+A276S+H358D+A364G+S388K;
[6249] C40S+V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[6250] C40V+V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[6251] A25W+V45L+L149R+S214E+V258P+A276S+A286E+A364G;
[6252] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+G394A;
[6253] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+A499L;
[6254] A25W+V45L+Q61K+L149R+S214E+V258P+A276S+A364G;
[6255] V45L+A117S+L149R+S214Q+T215V+V258P+A276S+H358D+A364G+S388K;
[6256] A25W+V45L+L149R+V258P+A276S+H358T+A364G+S388K;
[6257] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V+W495E;
[6258] A25W+V45L+A79C+L149R+V258P+A276S;
[6259] V45L+L149R+S214Q+V258P+A276S+V350L+A364G+S388K;
[6260] D11E+V45L+L149R+S214Q+V258P+A276S+A364G+S388K;
[6261] V45L+L149R+H219I+V258P+A276S+H358T+A364G+S388K;
[6262] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+C396V+D470T+R483V;
[6263] V45N+L149R+S214Q+V258P+A276S+A364G+S388K;
[6264] V45L+A117S+L149R+S214Q+H219V+V258P+A276S+H358D+A364G+S388K;
[6265] V45N+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K;
[6266] V45L+S92D+L149R+S214Q+V258P+A276S+A364G+S388K;
[6267] V45L+L149R+V258P+A276S+H358T+A364G;
[6268] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+L478P;
[6269] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+S481A;
[6270] V45L+A117S+L149R+S214Q+V258P+A276S+Q314A+A364G+S388K;
[6271] A25W+V45L+L149R+T211H+S214E+V258P+A276S+A364G;
[6272] A25W+V45L+L149R+S214E+H219V+V258P+A276S+A364G;
[6273] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S389V;
[6274] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+V393H;
[6275] V45L+A117S+L149R+S214Q+V258P+A276Q+H358D+A364G+S388K;
[6276] V45L+A117S+N127D+L149R+S214Q+V258P+A276S+H358D+A364G+S388K;
[6277] V45L+L149R+W250Y+V258P+A276S+H358T+A364G+S388K;
[6278] D9E+V45L+L149R+V258P+A276S+H358T+A364G+S388K;
[6279] V45L+L149R+H219V+V258P+A276S+H358T+A364G+S388K;
[6280] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+A472L;
[6281] A25W+V45L+L149R+V258P+A276S+A364G;
[6282] V45L+A117S+L149R+G187K+S214Q+V258P+A276S+A364G+S388K;
[6283] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+L478N;
[6284] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+V393R;
[6285] V45L+A117S+L149R+S214E+V258P+A276S+A364G+S388K;
[6286] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+T366V+S388K;
[6287] V45L+A117S+L149R+S214Q+V258P+A276S+H358T+A364G+S388K;
[6288] D11E+A25W+V45L+L149R+S214E+V258P+A276S+A364G;
[6289] V45L+T70R+A117S+L149R+C161V+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[6290] V45L+A117S+L149R+T211H+S214Q+V258P+A276S+H358D+A364G+S388K;
[6291] V45L+L149R+V258P+A276S+Q314A+H358T+A364G+S388K;
[6292] D11E+V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K;
[6293] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+G394Q;
[6294] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+N395D;
[6295] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+V393H;
[6296] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+S501E;
[6297] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+S528H;
[6298] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[6299] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388L;
[6300] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+C396L+D470T+R483V;
[6301] V45L+L149R+T180Q+S214Q+V258P+A276S+A364G+S388K;
[6302] V45L+D113T+L149R+S214Q+V258P+A276S+A364G+S388K;
[6303] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+T480L;
[6304] V45L+A93S+L149R+A252S+H334D;
[6305] V45L+A93S+L149R+V234P+A252S;
[6306] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388H;
[6307] A25W+V45L+Q61R+L149R+S214E+V258P+A276S+A364G;
[6308] V45L+A117S+L149R+S214Q+T215K+V258P+A276S+H358D+A364G+S388K+V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+S389H;
[6309] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+T366I+S388K;
[6310] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+N474G;
[6311] A25W+V45L+L149R+S214E+V258P+A276S+L281V+A364G;
[6312] D9E+A25W+V45L+L149R+S214E+V258P+A276S+A364G;
[6313] V45L+A117S+L149R+S214Q+T215K+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[6314] V45L+A117S+L149R+S214Y+V258P+A276S+H358D+A364G+S388K;
[6315] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+V393R;
[6316] V45L+Q61R+L149R+V258P+A276S+H358T+A364G+S388K;
[6317] V45L+L149R+S214Q+V258P+A276S+A364G+S388K;
[6318] V45L+D113T+L149R+V258P+A276S+H358T+A364G+S388K;
[6319] V45L+A117S+L149R+S214Q+V258P+A276S+A286S+A364G+S388K;
[6320] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388R;
[6321] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+A499Y;
[6322] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+V500V;
[6323] V45L+Q61R+L149R+S214Q+V258P+A276S+A364G+S388K;
[6324] V45L+L149R+S214E+V258P+A276S+H358T+A364G;
[6325] V45L+A117S+L149R+S214Q+V258P+A276Q+A364G+S388K;
[6326] V45L+L149R+V258P+A276S+L281V+A364G;
[6327] V45L+A117S+L149R+S214Q+W250Y+V258P+A276S+A364G+S388K;
[6328] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+T480N;
[6329] V45L+A117S+L149R+G187S+S214Q+V258P+A276S+A364G+S388K;
[6330] A25W+V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K;
[6331] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K;
[6332] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+N476N;
[6333] A25W+V45L+L149R+S214E+V258P+A276Q+A364G;
[6334] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+N476D;
[6335] V45L+L149R+S214Q+V258P+A276S+L281V+A364G;
[6336] V45L+A93S+L149R+A252S+H334D+A340G;
[6337] V45L+A93S+L149R+A252S+H334D;
[6338] V45L+A93S+L149R+A252S+H334D;
[6339] V45L+L149R+A252S+H334D;
[6340] V45L+N127D+L149R+V258P+A276S+A364G+S388K;
[6341] V45L+L149R+V258P+A276S+H358T+A364G+S388K;
[6342] V45L+L149R+V258P+A276S+A364G+S388K;
[6343] D9E+V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K;
[6344] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+S481S;
[6345] V45L+L149R+N168G+V258P+A276S+A364G;
[6346] V45L+L149R+T180Q+V258P+A276S+H358T+A364G+S388K;
[6347] V45L+L149R+G187L+V258P+A276S+A364G+S388K;
[6348] V45L+L149R+W250Y+V258P+A276S+A364G+S388K;
[6349] V45L+L149R+V258P+A276S+A286E+A364G+S388K;
[6350] V45L+L149R+V258P+A276S+S282N+A364G+S388K;
[6351] A25W+V45L+L149R+V258P+A276S+A364G+S388K;
[6352] V45L+L149R+S214Q+V258P+A276S+H358T+A364G;
[6353] V45L+L149R+S173Y+V258P+A276S+A364G;
[6354] V45L+A117S+L149R+S214Q+H219V+V258P+A276S+A364G+S388K;
[6355] V45L+A93S+L149R+A252S+H334D;
[6356] V45L+A93S+L149R+A252S+H334D+A340G;
[6357] V45L+L149R+S190E+D446T+R459V;
[6358] A25W+V45L+L149R+V258P+A276S+H358T;
[6359] A25W+V45L+S92D+L149R+S214E+V258P+A276S+A364G;
[6360] A25W+V45L+L149R+S214E+V258P+A276S+V350L+A364G;
[6361] A25W+V45L+L149R+S214Q+V258P+A276S+A364G;
[6362] V45L+L149R+N168G+V258P+A276S+A364G+S388K;
[6363] V45L+A117S+L149R+V258P+A276S+A364G+S388K;
[6364] A25W+V45L+L149R+V258P+A276S+H358T+A364G;
[6365] V45L+L149R+V258P+N260H+A276S+A364G+S388K;
[6366] V45L+L149R+T215I+V258P+A276S+A364G+S388K;
[6367] A25W+V45L+L149R+V258P+A276Q+A364G;
[6368] V45L+T70R+A117S+L149R+C161L+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[6369] A25W+V45L+L149R+S214E+V258P+A276S;
[6370] V45L+A117S+L149R+S214Q+V258P+A276S+A286S+H358D+A364G+S388K;
[6371] V45L+L149R+T211H+S214Q+V258P+A276S+A364G+S388K;
[6372] V45L+Q61K+L149R+V258P+A276S+H358T+A364G;
[6373] V45L+L149R+V258P+A276S+Q314A+H358T+A364G;
[6374] V45L+L149R+T180Q+V258P+A276S+A364G+S388K;
[6375] V45L+L149R+V258P+A276S+Q314A+A364G+S388K;
[6376] A25W+V45L+L149R+V258P+A276S+A286S+A364G;
[6377] V45L+L149R+S190E+D446T;
[6378] V45L+L149R+V258P+A276S+A364G;
[6379] V45L+L149R+A170S+V258P+A276S+A364G;
[6380] V45L+L149R+V258P+A276Q+A364G;
[6381] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V+C522A;
[6382] V45L+L149R+H219I+V258P+A276S+H358T+A364G;
[6383] V45L+L149R+V258P+A276S+V350L+A364G+S388K;
[6384] D11E+V45L+L149R+V258P+A276S+A364G+S388K;
[6385] V45L+D113T+L149R+V258P+A276S+A364G+S388K;
[6386] V45L+L149R+G187K+V258P+A276S+A364G+S388K;
[6387] M28P+V45L+L149R+V258P+A276S+A364G+S388K;
[6388] V45L+Q61R+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V;
[6389] A25W+V45L+L149R+S214Q+V258P+A276S;
[6390] V45L+A117S+L149R+S214Q+T215I+V258P+A276S+A364G+S388K;
[6391] A25W+V45L+L149R+V258P+A276S+S388K;
[6392] A25W+V45L+L149R+S214E+H219I+V258P+A276S+A364G;
[6393] V45L+A93S+L149R+V234P+A252S+H334D;
[6394] V45L+L149R+T211H+V258P+A276S+H358T+A364G+S388K;
[6395] A25W+V45L+A117S+L149R+S214E+V258P+A276S+A364G;
[6396] V45L+L149R+S173Y+V258P+A276S+A364G+S388K;
[6397] A25W+V45L+L149R+V258P+A276S+Q314A+A364G;
[6398] V45L+L149R+G187L+V258P+A276S+H358T+A364G;
[6399] V45L+L149R+T215V+V258P+A276S+H358T+A364G;
[6400] V45L+T70R+L149R+V258P+A276S+A364G+S388K;
[6401] V45L+N127D+L149R+V258P+A276S+A364G;
[6402] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+Q496R;
[6403] V45L+L149R+W250Y+V258P+A276S+A364G;
[6404] V45L+L149R+V258P+A276S+V350L+H358T+A364G;
[6405] D9E+V45L+L149R+V258P+A276S+H358T+A364G;
[6406] V45L+L149R+T211H+V258P+A276S+H358T+A364G;
[6407] A25W+V45L+L149R+W250Y+A276Q+A364G;
[6408] V45L+L149R+V258P+A276S+L281V+A364G+S388K;
[6409] V45L+L149R+V258P+A276S+S282N+H358T+A364G;
[6410] V45L+L149R+T215I+V258P+A276S+H358T+A364G;
[6411] A25W+V45L+L149R+S173Y+V258P+A276S+A364G;
[6412] V45L+Q61K+L149R+V258P+A276S+A364G+S388K;
[6413] V45L+L149R+T180Q+V258P+A276S+A364G;
[6414] V45L+A117S+L149R+A170S+S214Q+V258P+A276S+A364G+S388K;
[6415] V45L+Q61R+A117S+L149R+S214Q+V258P+A276S+A364G+S388K;
[6416] A25W+V45L+L149R+S214E+T215V+V258P+A276S+A364G;
[6417] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+V497P;
[6418] V45L+L149R+V258P+A276S+Q314A+A364G;
[6419] V45L+A117S+L149R+V258P+A276S+A364G;
[6420] V45L+A117S+L149R+V258P+A276S+H358T+A364G+S388K;
[6421] V45L+L149R+N168G+V258P+A276S+H358T+A364G+S388K;
[6422] A25W+V45L+Q61K+L149R+V258P+A276S+A364G;
[6423] V45L+L149R+S214E+V258P+A276S+L281V+A364G;
[6424] V45N+L149R+V258P+A276S+A364G+S388K;
[6425] V45L+L149R+V258P+A276S+A286E+H358T+A364G;
[6426] D9E+V45L+L149R+V258P+A276S+A364G+S388K;
[6427] V45L+S92D+L149R+V258P+A276S+A364G+S388K;
[6428] V45L+A117S+L149R+T180Q+S214Q+V258P+A276S+A364G+S388K;
[6429] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388H;
[6430] V45L+A117S+L149R+S214Q+T215V+V258P+A276S+A364G+S388K;
[6431] V45L+A117S+L149R+S214Q+V258P+A276S+V350L+A364G+S388K;
[6432] A25W+V45L+L149R+S214E+T215I+V258P+A276S+A364G;
[6433] V45L+N127D+L149R+V258P+A276S+H358T+A364G+S388K;
[6434] A25W+V45L+L149R+V258P+A276S+A286E+A364G;
[6435] V45L+L149R+N168G+V258P+A276S+L281V+A364G;
[6436] V45L+Q61R+L149R+V258P+A276S+H358T+A364G;
[6437] V45L+L149R+G187S+V258P+A276S+A364G+S388K;
[6438] V45L+L149R+V258P+A276S+L281V+Q314A+A364G;
[6439] V45L+L149R+V258P+A276S+L281V+H358T+A364G;
[6440] V45L+L149R+A170S+V258P+A276S+H358T+A364G;
[6441] V45L+L149R+A170S+V258P+A276S+A364G+S388K;
[6442] V45L+L149R+T215V+V258P+A276S+A364G+S388K;
[6443] V45L+L149R+V258P+A276Q+L281V+A364G;
[6444] V45L+T70R+A117S+L149R+S214Q+C243S+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V;
[6445] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V+C522V;
[6446] A25W+V45L+L149R+V258P+A276S+Q314A;
[6447] V45L+L149R+V258P+A276Q+H358T+A364G+S388K;
[6448] A25W+V45N+L149R+S214E+V258P+A276S+A364G;
[6449] V45L+L149R+V258P+A276S+A286E+A364G;
[6450] V45L+L149R+V258P+A276S+A286S+H358T+A364G;
[6451] A25W+V45L+L149R+G187S+V258P+A276S+A364G;
[6452] V45L+L149R+T180Q+V258P+A276S+L281V+A364G;
[6453] A25W+V45L+L149R+A276Q+L281V+A364G;
[6454] V45L+S92D+L149R+V258P+A276S+L281V+A364G;
[6455] V45L+Q61R+L149R+V258P+A276S+L281V+A364G;
[6456] V45L+L149R+A170S+V258P+A276S+L281V+A364G;
[6457] D11E+A25W+V45L+L149R+V258P+A276S+A364G;
[6458] A25W+V45L+Q61R+L149R+V258P+A276S+A364G;
[6459] A25W+V45L+L149R+T215V+V258P+A276S+A364G;
[6460] D9E+V45L+L149R+V258P+A276S+L281V+A364G;
[6461] A25W+V45L+L149R+V258P+A276S+V350L+A364G;
[6462] V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+A364G+S388K;
[6463] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+Y391V;
[6464] V45L+A117S+L149R+N168G+S214Q+V258P+A276S+A364G+S388K;
[6465] V45L+D113T+A117S+L149R+S214Q+V258P+A276S+A364G+S388K;
[6466] A25W+V45L+L149R+V258P+A276S+A286E;
[6467] A25W+V45L+L149R+V258P+A276S+L281V;
[6468] A25W+V45L+D113T+L149R+V258P+A276S;
[6469] V45L+L149R+H219V+V258P+A276S+L281V+A364G;
[6470] V45L+L149R+T180Q+V258P+A276S+H358T+A364G;
[6471] V45L+L149R+T215V+V258P+A276S+L281V+A364G;
[6472] A25W+V45L+L149R+V258P+A276S+S282N+A364G;
[6473] A25W+V45L+L149R+T215I+V258P+A276S+A364G;
[6474] A25W+V45L+L149R+H219I+V258P+A276S+A364G;
[6475] V45L+A117S+L149R+V258P+A276S+L281V+A364G;
[6476] D9E+A25W+V45L+L149R+V258P+A276S+A364G;
[6477] V45L+L149R+S214Y+V258P+A276S+A364G+S388K;
[6478] A25W+V45L+L149R+T180Q+V258P+A276S+A364G;
[6479] A25W+V45L+L149R+V258P+A276S+L281V+A364G;
[6480] V45L+N127D+L149R+V258P+A276S+L281V+A364G;
[6481] V45L+L149R+S173Y+V258P+A276S+H358T+A364G;
[6482] V45L+Q61R+L149R+V258P+A276S+A364G+S388K;
[6483] M28P+V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K;
[6484] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388A;
[6485] V45N+A117S+L149R+S214Q+V258P+A276S+A364G+S388K;
[6486] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+T477K;
[6487] A25W+V45L+L149R+T180Q+V258P+A276S;
[6488] A25W+V45L+L149R+V258P+A276S+A286S;
[6489] A25W+V45L+L149R+G187S+S214E+V258P+A276S+A364G;
[6490] V45L+L149R+V258P+A276S+L281V+A286E+A364G;
[6491] A25W+V45L+L149R+W250Y+V258P+A276S+A364G;
[6492] A25W+V45L+L149R+V258P+N260H+A276S+A364G;
[6493] V45L+L149R+V258P+A276S+L281V+V350L+A364G;
[6494] A25W+V45L+L149R+A170S+V258P+A276S+A364G;
[6495] V45L+L149R+V258P+A276S+L281V+A286S+A364G;
[6496] V45L+L149R+V258P+A276S+L281V+S282N+A364G;
[6497] D11E+V45L+L149R+V258P+A276S+L281V+A364G;
[6498] V45L+Q61K+L149R+V258P+A276S+L281V+A364G;
[6499] V45L+L149R+T215I+V258P+A276S+L281V+A364G;
[6500] A25W+V45L+S92D+L149R+V258P+A276S+A364G;
[6501] V45L+L149R+S214Y+V258P+A276S+L281V+A364G;
[6502] V45L+L149R+T211H+V258P+A276S+L281V+A364G;
[6503] A25W+V45L+L149R+G187L+V258P+A276S+A364G;
[6504] V45L+S92D+L149R+V258P+A276S+H358T+A364G;
[6505] V45L+L149R+G187L+A276Q+L281V+A364G;
[6506] V45L+L149R+A276Q+L281V+V350L+A364G;
[6507] V45L+L149R+A276Q+L281V+A364G+S388K;
[6508] V45L+A117S+L149R+S214Y+V258P+A276S+A364G+S388K;
[6509] A25W+V45L+S92D+L149R+V258P+A276S;
[6510] A25W+V45L+L149R+G187L+V258P+A276S;
[6511] A25W+V45L+L149R+W250Y+V258P+A276S;
[6512] V45L+D113T+L149R+V258P+A276S+A364G;
[6513] V45L+L149R+G187K+V258P+A276S+H358T+A364G;
[6514] V45L+L149R+N163H+V258P+A276S+L281V+A364G;
[6515] A25W+V45L+T70R+L149R+V258P+A276S+A364G;
[6516] V45L+L149R+S173Y+V258P+A276S+L281V+A364G;
[6517] V45L+L149R+G187L+V258P+A276S+L281V+A364G;
[6518] V45L+L149R+G187K+V258P+A276S+L281V+A364G;
[6519] V45L+L149R+W250Y+V258P+A276S+H358T+A364G;
[6520] V45L+L149R+T211H+V258P+A276S+A364G+S388K;
[6521] V45L+L149R+N163H+V258P+A276S+A364G+S388K;
[6522] V45L+T70R+L149R+A276Q+L281V+A364G;
[6523] V45L+S92D+L149R+A276Q+L281V+A364G;
[6524] V45L+D113T+L149R+A276Q+L281V+A364G;
[6525] V45L+L149R+A276Q+L281V+Q314A+A364G;
[6526] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+S389V;
[6527] A25W+V45L+Q61K+L149R+V258P+A276S;
[6528] D9E+A25W+V45L+L149R+V258P+A276S;
[6529] V45L+T70R+L149R+V258P+A276S+A364G;
[6530] V45L+L149R+V258P+A276S+A286S+A364G+S388K;
[6531] A25W+V45L+L149R+S214Y+V258P+A276S+A364G;
[6532] A25W+V45L+D113T+L149R+V258P+A276S+A364G;
[6533] V45L+T70R+L149R+V258P+A276S+L281V+A364G;
[6534] A25W+V45L+N127D+L149R+V258P+A276S+A364G;
[6535] V45L+T70R+L149R+V258P+A276S+H358T+A364G;
[6536] V45L+L149R+N163H+V258P+A276S+A364G;
[6537] V45L+L149R+T180Q+A276Q+L281V+A364G;
[6538] V45L+L149R+A276Q+L281V+A286S+A364G;
[6539] A25W+V45L+L149R+A170S+V258P+A276S;
[6540] A25W+V45L+T70R+L149R+V258P+A276S;
[6541] A25W+V45L+L149R+S214E+V258P+A276S+A286S+A364G;
[6542] V45L+L149R+V258P+A276S+A286S+H358T+A364G+S388K;
[6543] V45L+L149R+H219I+V258P+A276S+L281V+A364G;
[6544] A25W+V45L+A117S+L149R+V258P+A276S+A364G;
[6545] A25W+V45L+L149R+N168G+V258P+A276S+A364G;
[6546] V45L+L149R+N168G+A276Q+L281V+A364G;
[6547] V45L+L149R+S173Y+A276Q+L281V+A364G;
[6548] V45L+L149R+W250Y+A276Q+L281V+A364G;
[6549] V45L+A117S+L149R+S173Y+S214Q+V258P+A276S+A364G+S388K;
[6550] A25W+V45L+L149R+A276Q+A286E+A364G;
[6551] A25W+V45L+L149R+A276Q+A364G+S388K;
[6552] V45L+N127D+L149R+V258P+A276S+H358T+A364G;
[6553] A25W+V45L+L149R+V258P+A276S;
[6554] V45L+N127D+L149R+A276Q+L281V+A364G;
[6555] V45L+L149R+A276Q+L281V+A286E+A364G;
[6556] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+V500T;
[6557] A25W+V45L+A117S+L149R+V258P+A276S;
[6558] A25W+V45L+L149R+H219V+V258P+A276S+A364G;
[6559] V45L+L149R+S173Y+V258P+A276S+H358T+A364G+S388K;
[6560] D11E+V45L+L149R+V258P+A276S+H358T+A364G;
[6561] V45L+A79C+L149R+V258P+A276S+N355G+A364G+S388K;
[6562] A24K+V45L+L149R+V258P+A276S+A364G;
[6563] V45L+L149R+V258P+A276S+S282N+A364G;
[6564] V45L+A117S+L149R+A276Q+L281V+A364G;
[6565] V45L+L149R+N260H+A276Q+L281V+A364G;
[6566] V45L+A117S+L149R+T211H+S214Q+V258P+A276S+A364G+S388K;
[6567] A25W+V45L+L149R+N168G+V258P+A276S;
[6568] A25W+V45L+L149R+G187S+V258P+A276S;
[6569] A25W+V45L+L149R+V258P+A276S+V350L;
[6570] A25W+V45L+Q61R+L149R+V258P+A276S;
[6571] A25W+V45L+L149R+G187L+S214E+V258P+A276S+A364G;
[6572] V45L+L149R+G187S+V258P+A276S+L281V+A364G;
[6573] A25W+V45L+L149R+N163H+V258P+A276S+A364G;
[6574] A25W+V45L+L149R+G187K+V258P+A276S+A364G;
[6575] V45N+L149R+V258P+A276S+L281V+A364G;
[6576] V45L+L149R+A276Q+L281V+A364G;
[6577] V45L+L149R+V258P+N260H+A276S+H358T+A364G;
[6578] V45L+L149R+A276Q+S282N+A364G;
[6579] V45L+S92D+A117S+L149R+S214Q+V258P+A276S+A364G+S388K;
[6580] A25W+V45L+L149R+V258P+A276S+S282N;
[6581] A25W+V45L+L149R+S173Y+V258P+A276S;
[6582] A25W+V45L+L149R+A276Q+A286S+A364G;
[6583] V45L+D113T+L149R+V258P+A276S+L281V+A364G;
[6584] V45L+L149R+S214Q+V258P+A276S+L281V+A364G+S388K;
[6585] V45L+D113T+L149R+V258P+A276S+H358T+A364G;
[6586] A25W+V45L+L149R+T215V+V258P+A276S;
[6587] V45L+L149R+N168G+V258P+A276S+H358T+A364G;
[6588] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+A472L;
[6589] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+S473K;
[6590] A25W+V45L+L149R+T215I+V258P+A276S;
[6591] A25W+V45L+L149R+T211H+V258P+A276S;
[6592] A25W+V45L+L149R+V258P+A276Q;
[6593] V45L+L149R+S214Q+T215V+V258P+A276S+A364G+S388K;
[6594] V45L+L149R+N163H+V258P+A276S+H358T+A364G+S388K;
[6595] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+A499L;
[6596] V45L+L149R+V258P+A276S+V350L+A364G;
[6597] V45L+A79C+A117S+L149R+V258P+A276S+A364G+S388K;
[6598] A25W+V45L+D113T+L149R+A276Q+A364G;
[6599] A25W+V45N+L149R+V258P+A276S+A364G;
[6600] V45L+T70R+L149R+A276Q+A364G;
[6601] A25W+V45L+L149R+H219I+V258P+A276S;
[6602] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+V498I;
[6603] M28P+V45L+L149R+V258P+A276S+A364G;
[6604] A25W+V45L+T70R+L149R+A276Q+A364G;
[6605] A25W+V45L+L149R+A276Q+Q314A+A364G;
[6606] V45L+L149R+A170S+V258P+A276S+H358T+A364G+S388K;
[6607] A25W+V45L+L149R+S214Y+V258P+A276S;
[6608] V45L+L149R+S214Y+V258P+A276S+H358T+A364G;
[6609] V45L+L149R+A276Q+L281V+H358T+A364G;
[6610] A25W+V45L+L149R+H219V+V258P+A276S;
[6611] V45L+A117S+L149R+N163H+S214Q+V258P+A276S+A364G+S388K;
[6612] D11E+A25W+V45L+L149R+V258P+A276S;
[6613] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+N527H;
[6614] A25W+V45L+A117S+L149R+A276Q+A364G;
[6615] V45L+L149R+V258P+L281V+A364G;
[6616] A25W+V45L+L149R+G187L+A276Q+A364G;
[6617] V45N+L149R+V258P+A276S+H358T+A364G;
[6618] V45L+A117S+L149R+S214Q+V258P+A276S+N355G+H358D+A364G+S388K+D470T+R483V;
[6619] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388H+D470T+R483V;
[6620] A25W+V45L+L149R+A276Q+A364G;
[6621] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+R483V+V497E;
[6622] A25W+V45L+L149R+N163H+A276Q+A364G;
[6623] A25W+V45L+L149R+S173Y+A276Q+A364G;
[6624] A25W+V45L+L149R+A276Q+S282N+A364G;
[6625] A25W+V45L+L149R+A276Q+H358T+A364G;
[6626] A25W+V45L+L149R+T180Q+A276Q+A364G;
[6627] V45L+A117S+L149R+V258P+A276S+H358T+A364G;
[6628] V45L+L149R+A276Q+Q314A+A364G;
[6629] V45L+L149R+G187K+V258P+A364G;
[6630] V45L+L149R+A276Q+A286E+A364G;
[6631] A25W+V45L+N127D+L149R+A276Q+A364G;
[6632] A25W+V45L+L149R+A170S+A276Q+A364G;
[6633] A25W+V45L+N127D+L149R+V258P+A276S;
[6634] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+T477V;
[6635] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+G503L;
[6636] A25W+M28P+V45L+L149R+V258P+A276S+A364G;
[6637] V45L+L149R+A276Q+H358T+A364G;
[6638] A25W+V45L+L149R+N168G+A276Q+A364G;
[6639] A25W+V45L+L149R+N260H+A276Q+A364G;
[6640] V45L+A117S+L149R+G187L+S214Q+V258P+A276S+A364G+S388K;
[6641] V45L+A117S+L149R+N163H+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+L530R;
[6642] V45L+A117S+L149R+S214Q+T215K+V258P+A276S+A364G+S388K;
[6643] A25W+V45L+L149R+G187K+V258P+A276S;
[6644] A25W+M28P+V45L+L149R+V258P+A276S;
[6645] A25W+V45N+L149R+V258P+A276S;
[6646] V45L+A117S+L149R+S214Q+V258P+A276S+N355G+H358D+A364G+S388K+D470T;
[6647] V45L+N127D+L149R+A276Q+A364G;
[6648] V45L+L149R+W250Y+A276Q+A364G;
[6649] V45L+L149R+W250Y+V258P+A364G;
[6650] V45L+L149R+N163H+A276Q+L281V+A364G;
[6651] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+Q385C+S388K;
[6652] A25W+V45L+L149R+S214E+T215K+V258P+A276S+A364G;
[6653] M28P+V45L+L149R+V258P+A276S+L281V+A364G;
[6654] V45L+L149R+A276Q+A364G+S388K;
[6655] A25W+V45L+L149R+V258P+A364G;
[6656] M28P+V45L+L149R+V258P+A276S+H358T+A364G;
[6657] V45L+A117S+L149R+S214Q+V258P+A276S+N355G+H358D+A364G+S388K;
[6658] V45L+T70R+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K+G394A+D470T+R483V+C540V;
[6659] V45L+L149R+N168G+A276Q+A364G;
[6660] V45L+A117S+L149R+A276Q+A364G;
[6661] V45L+L149R+N163H+V258P+A276S+H358T+A364G;
[6662] V45L+L149R+T215K+V258P+A276S+H358T+A364G;
[6663] A24K+V45L+L149R+A276Q+A364G;
[6664] V45L+L149R+A276Q+A286S+A364G;
[6665] V45L+L149R+V258P+A364G;
[6666] V45L+L149R+H219I+V258P+A276S+A364G+S388K;
[6667] V45L+L149R+A170S+A276Q+A364G;
[6668] V45L+L149R+T180Q+A276Q+A364G;
[6669] V45L+L149R+A276Q+V350L+A364G;
[6670] V45L+L149R+V258P+S282N+A364G;
[6671] V45L+L149R+A276Q+A364G;
[6672] V45L+L149R+A276S+A364G;
[6673] V45L+L149R+T215K+V258P+A276S+A364G+S388K;
[6674] V45L+A117S+L149R+S214Q+V258P+A276S+N355G+A364G+S388K+D470T;
[6675] V45L+L149R+V258P+A276S;
[6676] A25W+V45L+L149R+A276S+A364G;
[6677] V45L+L149R+G187S+V258P+A364G;
[6678] V45L+S92D+L149R+V258P+A276S+H358T+A364G+S388K;
[6679] A25W+L149R+V258P+A276S+A364G;
[6680] V45L+L149R+G187L+A276Q+A364G;
[6681] A25W+V45L+V258P+A276S+A364G;
[6682] V45L+L149R+N260H+A276Q+A364G;
[6683] V45L+L149R+W250Y+V258R+A364G;
[6684] V45L+L149R+N163H+A276Q+A364G;
[6685] V45L+S92D+L149R+A276Q+A364G;
[6686] V45L+L149R+S173Y+A276Q+A364G;
[6687] V45L+S92D+L149R+V258P+A364G;
[6688] V45L+L149R+W250Y+V258P+A276S+L281V+A364G;
[6689] V45L+L149R+L281V+A364G;
[6690] V45L+D113T+L149R+A276Q+A364G;
[6691] L149R+V258P+A276S+A364G;
[6692] V45L+L149R+G187S+V258R+A364G;
[6693] V45L+V258P+A276S+A364G;
[6694] V45L+L149R+V258R+A364G+S388K;
[6695] A25W+V45L+L149R+A364G;
[6696] V45L+L149R+G187K+V258R+A364G;
[6697] V45L+L149R+V258P;
[6698] V45L+L149R+V258R+S282N+A364G;
[6699] V45L+L149R;
[6700] V45L+L149R+V258R+L281V+A364G;
[6701] V45L+L149R+A364G;
[6702] V45L+L149R+S214Q+V258P+A276S+N355G+A364G+S388K;
[6703] V45L+S92N+L149R+V258P+A364G;
[6704] V45L+A117S+L149R+S214Q+V258P+A276S+A286E+H358D+A364G+S388K;
[6705] A25W+V45L+L149R+S214E+V258P+A276S+N355G+A364G;
[6706] V45L+L149R+G187L+V258P+A276S+A364G;
[6707] V45L+L149R+V258R+A364G;
[6708] V45L+L149R+V258P+A364G+S388K;
[6709] A25W+V45L+L149R+A276Q+V350L+A364G;
[6710] V45L+L149R+H219V+V258P+A276S+A364G+S388K;
[6711] V45L+L149R+G187K+A364G;
[6712] V45L+L149R+G187S+A364G;
[6713] V45L+A117S+L149R+S214Q+V258P+A276S+N355G+A364G+S388K;
[6714] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+Y386G+S388K+D470T+R483V;
[6715] V45L+L149R+W250Y;
[6716] V45L+S92N+L149R+V258R+A364G;
[6717] A25W+V45L+L149R+V258P+A276S+N355G+A364G;
[6718] V45L+L149R+V258P+A276S+N355G+A364G+S388K;
[6719] V45L+L149R+G187S;
[6720] V45N+L149R;
[6721] V45L+L149R+S282N;
[6722] L149R+A364G;
[6723] Y386G;
[6724] V258P+A276Q;
[6725] V258P+A276S;
[6726] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394D+D470T+R483V;
[6727] A25W+L149R;
[6728] V45L+A276S;
[6729] V45L+S92D+L149R;
[6730] A25W+A276S;
[6731] Q385C;
[6732] V45L+L149R+W250Y+A364G;
[6733] V45L+A276Q;
[6734] V45L+V258P;
[6735] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+Y386G+S388K;
[6736] A25W+V258P;
[6737] A25W+A276Q;
[6738] L149R+W250Y;
[6739] V45L+L149R+V258P+A276S+L281V+N355G+A364G;
[6740] V45L+S388K;
[6741] V45L+L149R+V258P+A276S+N355G+H358T+A364G;
[6742] V45L+A364G;
[6743] V45N+V258P;
[6744] A276S;
[6745] V258P+S388K;
[6746] A25W+V45L;
[6747] A276Q+S388K;
[6748] A276C;
[6749] A276Q;
[6750] A276F;
[6751] W250Y+A276Q;
[6752] A79C;
[6753] A276S+S388K;
[6754] A276Q+L281V;
[6755] V45L+L149R+V258P+A276S+N355G+A364G;
[6756] A276N;
[6757] W250Y+A276S;
[6758] A25W+S388K;
[6759] A276S+L281V;
[6760] G187S+A276Q;
[6761] A25W+V45L+L149R+V258P+A276S+N355G;
[6762] V45L;
[6763] S92D+A276S;
[6764] S19T;
[6765] L149R+V258R;
[6766] V45N+S388K;
[6767] A25W+V45L+S92D+L149R+A276Q+A364G;
[6768] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+S501E H358D;
[6769] A25W+A364G;
[6770] V258P+L281V;
[6771] L149R;
[6772] V45L+L149R+H219V+V258P+A276S+H358T+A364G;
[6773] A25W;
[6774] V258R+A276S;
[6775] V45N;
[6776] G187S+A276S;
[6777] G187K+A276S;
[6778] I469T;
[6779] V45L+S92D;
[6780] V45L+L281V;
[6781] V45N+W250Y;
[6782] V258R+A276Q;
[6783] V45L+V258R;
[6784] W250Y+S388K;
[6785] A25W+V45L+L149R+A276Q+N355G+A364G;
[6786] V45N+G187K;
[6787] A25W+V45L+L149R+S214E+V258P+A276S+Q314A+A364G;
[6788] S388A;
[6789] A276T;
[6790] A25W+V258R;
[6791] G187K+S388K;
[6792] A25W+S92D;
[6793] L281V+S388K;
[6794] V45N+V258R;
[6795] S388H;
[6796] S92D;
[6797] D525L;
[6798] S214Q;
[6799] L281V+A364G;
[6800] A364G;
[6801] S388L;
[6802] S388R;
[6803] S473G;
[6804] S92D+A364G;
[6805] A25W+G187S;
[6806] A25W+G187K;
[6807] W250Y+V258P;
[6808] S92D+V258P;
[6809] S389V;
[6810] A20H;
[6811] W495E;
[6812] G187K+W250Y;
[6813] Y386Y;
[6814] V393H;
[6815] G187L;
[6816] Q61K;
[6817] V45N+S92D;
[6818] G187S+A364G;
[6819] G187S+L281V;
[6820] G187S;
[6821] A286E;
[6822] A276Y;
[6823] V258P;
[6824] Q496E;
[6825] G394A;
[6826] V393R;
[6827] G187S+S388K;
[6828] T366V;
[6829] S389S;
[6830] S92N;
[6831] N527H;
[6832] Q384A;
[6833] V497D;
[6834] D470T;
[6835] A18V;
[6836] Q496Q;
[6837] Q496R;
[6838] S214E;
[6839] P362P;
[6840] S389H;
[6841] V258R;
[6842] A276D;
[6843] L281V;
[6844] V451;
[6845] A117C;
[6846] N395N;
[6847] Y391Y;
[6848] A24H;
[6849] A472I;
[6850] D470K;
[6851] S473K;
[6852] S473S;
[6853] W495I;
[6854] V497E;
[6855] A24K;
[6856] V45T;
[6857] L471R;
[6858] A472L;
[6859] A20P;
[6860] N395D;
[6861] G394D;
[6862] G394Q;
[6863] G187S+V258R;
[6864] S92D+G187S;
[6865] V45C;
[6866] N476N;
[6867] G207G;
[6868] A364A;
[6869] D470A;
[6870] N474G;
[6871] D470V; and wherein the variant has xylanse activity and wherein the variant has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%, but less than 100% sequence identity to SEQ ID NO: 1, and wherein the variants have increased thermostability measured as increased melting temperature measured by TSA of at least 0.5° C. compared to the xylanase of SEQ ID NO: 1.
[6872] Paragraph 9. The xylanase variant according to any one of the preceding paragraphs, wherein the variant comprises at least one of the following substitutions or combinations of substitutions: V45L+A79C+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V;
[6873] V45L+A79C+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+R483V;
[6874] V45L+Q61K+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[6875] V45L+D95N+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+G394A+D470T;
[6876] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+G394A+D470T+R483V;
[6877] V45L+A93T+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T+A499Y;
[6878] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+Q384A+S388K+D470T+R483V;
[6879] V45L+A79C+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K;
[6880] V45L+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T+R483V;
[6881] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470T;
[6882] V45L+A79C+A117S+L149R+S214Q+V258P+A276S+A364G+S388K+D470T;
[6883] V45L+D95N+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+S473G;
[6884] V45L+T70R+D95N+A117S+L149R+S214Q+V258P+A276S+L356M+H358D+A364G+S388K;
[6885] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+D470A;
[6886] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+L478N;
[6887] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+N395D;
[6888] V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K+T477K;
[6889] V45L+A117S+L149R+S214Q+V258P+A276S+L281V+H358D+A364G+S388K;
[6890] D11E+V45L+A117S+L149R+S214Q+V258P+A276S+H358D+A364G+S388K;
[6891] V45L+L149R+V258P+A276S+H358T+A364G;
[6892] A25W+V45L+L149R+V258P+A276S+A364G;
[6893] V45L+L149R+S214Q+V258P+A276S+A364G+S388K;
[6894] V45L+L149R+V258P+A276S+L281V+A364G;
[6895] V45L+N127D+L149R+V258P+A276S+A364G+S388K;
[6896] V45L+L149R+V258P+A276S+H358T+A364G+S388K;
[6897] V45L+L149R+V258P+A276S+A364G+S388K;
[6898] V45L+L149R+W250Y+V258P+A276S+A364G+S388K;
[6899] V45L+L149R+V258P+A276S+A286E+A364G+S388K;
[6900] V45L+L149R+V258P+A276S+S282N+A364G+S388K;
[6901] V45L+L149R+S214Q+V258P+A276S+H358T+A364G;
[6902] A25W+V45L+L149R+V258P+A276Q+A364G;
[6903] V45L+L149R+V258P+A276S+A364G;
[6904] A25W+V45L+L149R+W250Y+A276Q+A364G;
[6905] A25W+V45L+L149R+A276Q+L281V+A364G;
[6906] A25W+V45L+L149R+A276Q+A286E+A364G;
[6907] A25W+V45L+L149R+A276Q+A364G+S388K;
[6908] V45L+L149R+V258P+L281V+A364G;
[6909] A25W+V45L+L149R+A276Q+A364G;
[6910] V45L+L149R+V258P+A364G;
[6911] V45L+L149R+V258P+S282N+A364G;
[6912] V45L+L149R+A276Q+A364G;
[6913] V45L+L149R+A276S+A364G;
[6914] V45L+L149R;
[6915] V45L+L149R+A364G;
[6916] V45L+L149R+V258R+A364G;
[6917] V258P+A276Q;
[6918] V258P+A276S;
[6919] V45L+A276S;
[6920] V45L+A276Q;
[6921] L149R+W250Y;
[6922] V258P+S388K;
[6923] A276Q+S388K;
[6924] W250Y+A276Q;
[6925] A276S+S388K;
[6926] A276Q+L281V;
[6927] W250Y+A276S;
[6928] A276S+L281V;
[6929] G187S+A276Q;
[6930] V45L+L281V;
[6931] V45L;
[6932] L149R;
[6933] A79C;
[6934] V45N;
[6935] V45L+D11E;
[6936] L149R+S388K;
[6937] L149R+D11E;
[6938] A364G+D11E;
[6939] S388K+D11E; and wherein the variant has xylanse activity and wherein the variant has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%, but less than 100% sequence identity to SEQ ID NO: 1, and wherein the variants have increased thermostability measured as increased melting temperature measured by n-DSF of at least 0.5° C. compared to the xylanase of SEQ ID NO: 1.
[6940] Paragraph 10. The xylanase variant according to any one of the preceding paragraphs, wherein the parent polypeptide has at least 60%, e.g., at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% but less than 100% sequence identity to the polypeptide of SEQ ID NO: 1.
[6941] Paragraph 11. The xylanase variant according to any one of the preceding paragraphs, wherein said parent polypeptide comprises or consists of the polypeptide of SEQ ID NO: 1.
[6942] Paragraph 12. The xylanase variant according to any one of the preceding paragraphs, wherein the substitution is selected from the group consisting of A, C, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W and Y, with the proviso that the substituted amino acid residue is different from the naturally-occurring amino acid residue in that position.
[6943] Paragraph 13. The xylanase variant according to any one of the preceding paragraphs, wherein the number of substitutions is 1-20, e.g., 1-10 and 1-5, such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 substitutions.
[6944] Paragraph 14. A polynucleotide encoding the xylanase variant of any of paragraphs 1-13.
[6945] Paragraph 15. A nucleic acid construct comprising the polynucleotide of paragraph 14.
[6946] Paragraph 16. An expression vector comprising the polynucleotide of paragraph 14.
[6947] Paragraph 17. A host cell comprising the polynucleotide of paragraph 14.
[6948] Paragraph 18. The host cell according to paragraph 17, wherein the host cell is a yeast cell, particularly a Saccharomyces, such as Saccharomyces cerevisiae.
[6949] Paragraph 19. A method of producing a xylanase variant of any one of the preceding paragraphs, comprising cultivating the host cell of paragraphs 17 or 18 under conditions conducive for production of the polypeptide.
[6950] Paragraph 20. The method according to paragraph 19, further comprising recovering the polypeptide.
[6951] Paragraph 21. A method of obtaining a xylanase variant, comprising (a) introducing into a parent xylanase a substitution at one or more positions corresponding to positions 45, 149, 364, 258, 276, and 388 of SEQ ID NO: 1, wherein the xylanase variant has xylanase activity and has at least 60, e.g., at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to SEQ ID NO: 1; and (b) optionally recovering the xylanase variant.
[6952] Paragraph 22. The method according to paragraph 21 further comprising (a) substitution at one or more positions corresponding to positions to 9, 11, 18, 19, 20, 24, 25, 28, 40, 60, 61, 69, 70, 77, 79, 92, 93, 95, 113, 117, 127, 161, 163, 168, 170, 173, 180, 187, 190, 192, 211, 214, 215, 219, 234, 243, 250, 252, 260, 281, 282, 286, 314, 334, 340, 350, 355, 356, 358, 366, 375, 384, 385, 386, 389, 391, 393, 394, 395, 396, 446, 459, 468, 469, 470, 471, 472, 473, 474, 476, 477, 478, 480, 481, 483, 484, 495, 496, 497, 498, 499, 500, 501, 503, 522, 525, 526, 527, 528, 529, 530, and 540 of SEQ ID NO: 1, wherein the xylanase variant has xylanase activity and has at least 60, e.g., at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to SEQ ID NO: 1; and (b) optionally recovering the xylanase variant.
[6953] Paragraph 23. A whole broth formulation or cell culture composition comprising a xylanase variant of any of paragraphs 1-13.
[6954] Paragraph 24. A composition comprising the xylanase variant of paragraphs 1-13.
[6955] Paragraph 25. The composition according to paragraph 24, further comprising one or more enzymes selected from the group consisting of: cellulase, hemicellulase, cellulases (EC 3.2.1.4), xylanases (EC 3.2.1.8) arabinofuranosidases (EC 3.2.1.55 (Non-reducing end alpha-L-arabinofuranosidases); EC 3.2.1.185 (Non-reducing end beta-L-arabinofuranosidases) cellobiohydrolase I (EC 3.2.1.150), cellobiohydrolase II (E.C. 3.2.1.91), cellobiosidase (E.C. 3.2.1.176), beta-glucosidase (E.C. 3.2.1.21), beta-xylosidases (EC 3.2.1.37) and combination thereof.
[6956] Paragraph 26. A method for increasing the starch yield and/or gluten yield from corn kernels in a wet milling process, the method comprising contacting corn kernels or a fraction of the corn kernels, particularly a fiber rich fraction, with an effective amount of a xylanase variant of paragraph 1-13 and optionally one or more hydrolytic enzymes.
[6957] Paragraph 27. The method according to paragraph 26, comprising the steps of:
[6958] a) soaking the corn kernels in water to produce soaked kernels;
[6959] b) grinding the soaked kernels to produce ground kernels;
[6960] c) separating germ from the ground kernels to produce a corn kernel mass comprising fiber, starch and gluten; and
[6961] d) subjecting the corn kernel mass to a fiber washing procedure separating starch and gluten from the fiber;
[6962] wherein at least a xylanase variant of paragraph 1-13 is present/added before or during step d).
[6963] Paragraph 28. The method of paragraph 27, further comprising the steps of:
[6964] e) separating the starch from the gluten; and optionally
[6965] f) washing the starch.
[6966] Paragraph 29. The method according to any of paragraphs 26-28, wherein the one or more hydrolytic enzymes comprises one or more cellulases.
[6967] Paragraph 30. The method according to paragraph 29, wherein the cellulase(s) comprises one or more enzyme selected from the group consisting of an endoglucanase (EG), and a cellobiohydrolase (CBH).
[6968] Paragraph 31. The method of paragraph 30, wherein the cellulase(s) comprises one or more enzyme selected from the group consisting of an endoglucanase, a cellobiohydrolase I, a cellobiohydrolase II, or a combination thereof.
[6969] Paragraph 32. The method according to any of the paragraphs 27-31, wherein the corn kernel mass comprising fiber, starch and gluten from step c) is subjected to a further grinding step, preferably a fine grinding step before the fiber washing procedure in step d).
[6970] Paragraph 33. The method according to any of the preceding paragraphs 26-32, wherein the effective amount of one or more hydrolytic enzymes admixed with one or more fractions of said corn kernel mass, is between 0.005-0.5 kg enzyme protein/metric tonne corn kernels entering the wet milling process.
[6971] Paragraph 34. Use of xylanase variant of paragraphs 1-13 in a method to increase the starch yield and/or gluten yield from corn kernels in a wet milling process.
[6972] Paragraph 35. A process for producing fermentation products from starch-containing material comprising the steps of:
[6973] i) saccharifying the starch-containing material using a carbohydrate-source generating enzyme at a temperature below the initial gelatinization temperature;
[6974] ii) fermenting using a fermenting organism;
[6975] wherein at least one or more xylanase variant(s) of paragraphs 1-13 are present or added during fermentation or simultaneous saccharification and fermentation.
[6976] Paragraph 36. A process for producing a fermentation product from starch-containing material comprising the steps of: (a) liquefying starch-containing material above the initial gelatinization temperature of said starch-containing material in the presence of an alpha amylase; (b) saccharifying the liquefied material; and (c) fermenting with a fermenting organism; wherein step (b) is carried out in the presence of at least a glucoamylase and the variant alpha-amylase of any of paragraphs 1-13.
[6977] Paragraph 37. The process of any of paragraphs 35-36, wherein saccharification and fermentation is carried out simultaneously.
[6978] Paragraph 38. The process of any of the paragraphs 35-37, wherein the host cell of paragraph 18 is applied as the fermenting organism.
[6979] Paragraph 39. The process of paragraph 38, wherein the host cell further is expressing a glucoamylase.
[6980] Paragraph 40. The process of any of paragraphs 35-39, wherein the starch-containing material is corn and the fermentation product is ethanol.
EXAMPLES
Example 1: Construction of Variants by Site-Directed Mutagenesis
[6981] Site-directed variants were constructed of the Chryseobacterium sp., 10696 xylanase (SEQ ID NO: 1), comprising specific substitutions according to the invention. SEQ ID NO: 2 encodes the Chryseobacterium sp., 10696 xylanase of SEQ ID NO: 1. The variants were made by traditional cloning of DNA fragments (Sambrook et al., Molecular Cloning: A Laboratory Manual, 2nd Ed., Cold Spring Harbor, 1989) using PCR together with properly designed mutagenic oligonucleotides that introduced the desired mutations in the resulting sequence. Mutagenic oligos were designed corresponding to the DNA sequence flanking the desired site(s) of mutation, separated by the DNA base pairs defining the insertions/deletions/substitutions, and purchased from an oligo vendor such as Macrogen, Inc.
Example 2: Protein Thermal Unfolding Analysis (TSA, Thermal Shift Assay) of Culture Supernatant Samples
[6982] Culture supernatants grown in 96-well plate (MicroAmpR fast 96-well plate, Applied Biosystems) was clarified by centrifugation at 3000×g for 30 min at 4° C. In a 96-well PCR plate, pre-clarified supernatant (5 μl) was mixed with reporter dye solution (2.5 μl) [1 μl of Sypro orange (S5692, Sigma) in 125 μl of MilliQ water]. Final reaction volume was made upto 30 μl by adding 22.5 μl of dilution buffer [sodium acetate buffer (50 mM) was made by adding 4.1 g of sodium acetate (Sigma, S2889) in 1 L of Milli-Q water and adjusting the pH to 4.0 using acetic acid]. A plate was sealed with a plate sealer (MicroAmpR optical adhesive film, Applied Biosystems) and kept in a TSA instrument. In each run, purified xylanase-WT and culture supernatant-WT were used as controls. The results in table 1 show that the xylanase variants have improved thermostability relative to the wild-type xylanase (SEQ ID NO: 1).
TABLE-US-00002 TABLE 1 TSA data of xylanase variants of SEQ ID NO: 1 Tm Variant(s) (° C.) WT 44.3 V45L + Q61K + T70R + A117S + L149R + S214Q + V258P + 61.4 A276S + L281V + A286E + H358D + A364G + Q384A + S388K + V393H + D470T + R483V V45L + Q61K + T70R + A117S + L149R + S214Q + V258P + 61.4 A276S + L281V + H358D + A364G + Q384A + S388K + G394Q + D470T + R483V V45L + Q61K + T70R + A117S + L149R + S214Q + V258P + 61.3 A276S + L281V + H358D + A364G + Q384A + S388K + G394A + D470T + R483V V45L + Q61K + T70R + A117S + L149R + S214Q + V258P + 61.3 A276S + L281V + H358D + A364G + Q384A + S388K + V393H + D470T + R483V V45L + Q61K + T70R + A117S + L149R + S214Q + V258P + 61.2 A276S + L281V + H358D + A364G + Q384A + S388K + V393H + D470T + R483V V45L + Q61K + T70R + A117S + L149R + S214Q + V258P + 61.1 A276S + L281V + H358D + A364G + Q384A + S388K + G394A + D470T + R483V V45L + Q61K + T70R + A117S + L149R + S214Q + V258P + 61.1 A276S + L281V + H358D + A364G + Q384A + S388K + V393H + D470T + R483V V45L + Q61K + T70R + A117S + L149R + S214Q + V258P + 61.1 A276S + L281V + H358D + A364G + Q384A + S388K + G394A + D470T + R483V V45L + Q61K + T70R + A117S + L149R + S214Q + V258P + 61.1 A276S + L281V + A286E + H358D + A364G + Q384A + S388K + V393H + D470T + R483V V45L + Q61K + T70R + A117S + L149R + S214Q + V258P + 61.0 A276S + L281V + H358D + A364G + Q384A + S388K + V393H + D470T + R483V V45L + Q61K + T70R + A117S + L149R + S214Q + V258P + 61.0 A276S + L281V + H358D + A364G + Q384A + S388K + G394A + D470T + R483V V45L + A79C + A117S + L149R + S214Q + V258P + A276S + 60.6 H358D + A364G + S388K + D470T + L530R V45L + A79C + A117S + L149R + S214Q + V258P + A276S + 60.6 H358D + A364G + S388K + D470T + R483V V45L + T70R + A117S + L149R + S214Q + V258P + A276S + 60.5 L281V + H358D + A364G + S388K + G394A + D470T + R483V V45L + T70R + A117S + L149R + S214Q + V258P + A276S + 60.5 L281V + H358D + A364G + S388K + G394A + D470T + R483V V45L + T70R + A117S + L149R + S214Q + V258P + A276S + 60.4 L281V + H358D + A364G + S388K + G394A + D470T + R483V V45L + T70R + A117S + L149R + S214Q + V258P + A276S + 60.4 L281V + H358D + A364G + S388K + G394A + D470T + R483V V45L + T70R + A117S + L149R + S214Q + V258P + A276S + 60.3 L281V + H358D + A364G + S388K + G394A + D470T + R483V V45L + T70R + A117S + L149R + S214Q + V258P + A276S + 60.3 L281V + H358D + A364G + S388K + G394A + D470T + R483V V45L + Q61K + A117S + L149R + S214Q + V258P + A276S + 60.2 L281V + H358D + A364G + S388K + G394A + D470T + R483V + L530R V45L + T70R + A117S + L149R + S214Q + V258P + A276S + 60.2 L281V + H358D + A364G + S388K + G394A + D470T + R483V V45L + T70R + A117S + L149R + S214Q + V258P + A276S + 60.2 L281V + H358D + A364G + S388K + G394A + D470T + R483V V45L + T70R + A117S + L149R + S214Q + V258P + A276S + 60.1 L281V + H358D + A364G + S388K + G394A + D470T + R483V V45L + T70R + A117S + L149R + S214Q + V258P + A276S + 60.1 L281V + H358D + A364G + S388K + G394A + D470T + R483V V45L + Q61K + A117S + L149R + S214Q + V258P + A276S + 59.9 L281V + H358D + A364G + S388K + G394A + D470T + L530R V45L + Q61K + A117S + L149R + S214Q + V258P + A276S + 59.7 L281V + H358D + A364G + S388K + G394A + D470T + R483V + L530R V45L + Q61K + A117S + L149R + S214Q + V258P + A276S + 59.6 L281V + H358D + A364G + S388K + G394A + D470T + R483V + L530R V45L + Q61K + A117S + L149R + S214Q + V258P + A276S + 59.6 L281V + H358D + A364G + S388K + D470T + R483V + L530R V45L + Q61K + A117S + L149R + S214Q + V258P + A276S + 59.6 L281V + H358D + A364G + S388K + G394A + D470T + R483V + L530R V45L + Q61K + A117S + L149R + S214Q + V258P + A276S + 59.6 L281V + H358D + A364G + S388K + D470T + R483V + L530R V45L + A117S + L149R + G187K + S214Q + V258P + A276S + 59.5 A286E + H358D + A364G + Q384A + S388K + V393H + D470T + R483V V45L + A117S + L149R + G187K + S214Q + V258P + A276S + 59.4 A286E + H358D + A364G + Q384A + S388K + N395D + D470T + R483V V45L + A117S + L149R + G187K + S214E + T215I + V258P + 59.2 A276S + A286E + H358D + A364G + S388K + V393H + D470T + R483V V45L + A117S + L149R + G187K + S214E + T215I + V258P + 59.1 A276S + A286E + H358D + A364G + S388K + N395D + D470T + R483V V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 59.1 A364G + Q385C + S388K + D470T + R483V V45L + Q61K + A117S + L149R + S214Q + V258P + A276S + 58.9 H358D + A364G + S388K + D470T + R483V V45L + A79C + A117S + L149R + S214Q + V258P + A276S + 58.9 A364G + S388K + D470T + R483V V45L + A117S + L149R + S214Q + V258P + A276S + L281V + 58.8 H358D + A364G + S388K + D470T + R483V V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 58.8 A364G + T366I + S388K + D470T + R483V V45L + T70R + A117S + L149R + S214Q + V258P + A276S + 58.8 L281V + H358D + A364G + S388K + G394A + D470T + R483V V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 58.8 A364G + Q384A + S388K + D470T + L530R V45L + Q61K + A117S + L149R + S214Q + V258P + A276S + 58.8 H358D + A364G + S388K + D470T + L530R V45L + T70R + A117S + L149R + S214Q + V258P + A276S + 58.8 H358D + A364G + S388K + D470T + R483V V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 58.8 A364G + S388K + V393H + D470T + R483V V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 58.8 A364G + S388K + G394A + D470T + R483V V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 58.7 A364G + S388K + V393H + D470T + L530R V45L + A117S + L149R + S214Q + V258P + A276S + A286E + 58.7 H358D + A364G + S388K + D470T + R483V D11E + V45L + A117S + L149R + S214Q + V258P + A276S + 58.7 H358D + A364G + S388K + D470T + R483V V45L + T70R + A117S + L149R + S214Q + V258P + A276S + 58.7 L281V + H358D + A364G + S388K + G394A + C468V + D470T + R483V V45L + A79C + A117S + L149R + S214Q + V258P + A276S + 58.7 H358D + A364G + S388K + D470T V45L + A79C + L149R + S214E + V258P + A276S + A364G + 58.6 S388K V45L + A117S + L149R + G187L + S214Q + V258P + A276S + 58.6 H358D + A364G + S388K + D470T + L530R V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 58.6 A364G + Q384A + S388K + D470T + R483V V45L + A117S + L149R + G187K + S214Q + V258P + A276S + 58.6 H358D + A364G + S388K + D470T + R483V V45L + A117S + L149R + S214Q + V258P + A276S + L281V + 58.6 H358D + A364G + S388K + D470T + L530R V45L + A117S + L149R + S214E + V258P + A276S + H358D + 58.6 A364G + S388K + D470T + R483V V45L + A117S + L149R + G187L + S214Q + V258P + A276S + 58.6 H358D + A364G + S388K + D470T + R483V V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 58.6 A364G + S388K + G394Q + D470T + R483V V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 58.5 A364G + S388K + G394A + D470T + L530R V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 58.5 A364G + T366V + S388K + D470T + L530R V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 58.5 A364G + S388K + G394Q + D470T + L530R V45L + A117S + L149R + S214Q + V258P + A276S + S282N + 58.5 H358D + A364G + S388K + D470T + R483V V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 58.5 A364G + S388K + N395D + D470T + R483V V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 58.5 A364G + S388K + D470T + N476D + R483V V45L + A117S + L149R + S214Q + V258P + A276S + V350L + 58.5 H358D + A364G + S388K + D470T + R483V V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 58.5 A364G + S388K + D470T + T477K + R483V V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 58.5 A364G + S388K + D470T + R483V + Q496R V45L + T70R + A117S + L149R + S214Q + V258P + A276S + 58.5 L281V + H358D + A364G + S388K + G394A + C468A + D470T + R483V V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 58.5 A364G + S388K + D470T + R483V + W495E V45L + A117S + L149R + S214Q + V258P + A276S + A286E + 58.4 H358D + A364G + S388K + D470T + L530R V45L + A117S + L149R + G187K + S214Q + V258P + A276S + 58.4 H358D + A364G + S388K + D470T + L530R V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 58.4 A364G + S388K + Y391V + D470T + R483V V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 58.4 A364G + S388K + D470T + R483V D9E + V45L + A117S + L149R + S214Q + V258P + A276S + 58.4 H358D + A364G + S388K + D470T + L530R V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 58.4 A364G + S388K + D470T + T477V + R483V V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 58.4 A364G + S388K + D470T + N476N + R483V V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 58.4 A364G + S388K + V393R + D470T + R483V V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 58.3 A364G + S388K + D470T + T480L + L530R V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 58.3 A364G + S388K + D470T + S481A + L530R V45L + A117S + L149R + S214Q + W250Y + V258P + A276S + 58.3 H358D + A364G + S388K + D470T + R483V V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 58.3 A364G + S388K + D470T + S481S + R483V V45L + A117S + L149R + S173Y + S214Q + V258P + A276S + 58.3 H358D + A364G + S388K + D470T + R483V V45L + T70R + A117S + L149R + S214Q + C243V + V258P + 58.3 A276S + L281V + H358D + A364G + S388K + G394A + D470T + R483V V45L + A117S + L149R + T180Q + S214Q + V258P + A276S + 58.2 H358D + A364G + S388K + D470T + L530R D11E + V45L + A117S + L149R + S214Q + V258P + A276S + 58.2 H358D + A364G + S388K + D470T + L530R V45L + A117S + L149R + S214E + V258P + A276S + H358D + 58.2 A364G + S388K + D470T + L530R V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 58.2 A364G + S388K + D470T + N476D + L530R V45L + A117S + L149R + S214Q + V258P + A276S + A286S + 58.2 H358D + A364G + S388K + D470T + R483V V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 58.2 A364G + S388K + D470T + R483V + Q496Q V45L + A117S + L149R + S214Q + V258P + A276Q + H358D + 58.2 A364G + S388K + D470T + R483V V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 58.2 A364G + S388K + D470T + R483V + Q496E V45L + Q61R + A117S + L149R + S214Q + V258P + A276S + 58.2 H358D + A364G + S388K + D470T + L530R V45L + A117S + L149R + S214Q + V258P + A276S + Q314A + 58.2 H358D + A364G + S388K + D470T + L530R V45L + A117S + L149R + S214Q + V258P + A276Q + H358D + 58.2 A364G + S388K + D470T + L530R V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 58.2 A364G + S388K + D470T + L478P + R483V A25W + V45L + A117S + L149R + S214Q + V258P + A276S + 58.2 H358D + A364G + S388K + D470T + R483V V45L + A117S + L149R + T180Q + S214Q + V258P + A276S + 58.2 H358D + A364G + S388K + D470T + R483V V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 58.2 A364G + S388K + D470T + R483V + L484K V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 58.1 A364G + S388K + D470T + N474G + L530R V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 58.1 A364G + S388K + N395D + D470T + L530R V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 58.1 A364G + T366V + S388K + D470T + R483V V45L + A117S + L149R + N168G + S214Q + V258P + A276S + 58.1 H358D + A364G + S388K + D470T + R483V V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 58.1 A364G + S388K + D470T + R483V + L484S V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 58.1 A364G + S388K + D470T + L530R V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 58.1 A364G + S388K + D470T + R483V + L484D V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 58.1 A364G + S388K + D470T + R483V + S528H V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 58.1 A364G + S388K + D470T + R483V + S501N V45L + A117S + L149R + S173Y + S214Q + V258P + A276S + 58.1 H358D + A364G + S388K + D470T + L530R V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 58.0 A364G + S388K + D470T + R483V + A499L V45L + S92D + A117S + L149R + S214Q + V258P + A276S + 58.0 H358D + A364G + S388K + D470T + R483V V45L + A117S + L149R + S214Q + V258P + A276S + Q314A + 58.0 H358D + A364G + S388K + D470T + R483V V45L + A79C + L149R + S214Q + V258P + A276S + A364G + 58.0 S388K V45L + A117S + L149R + S214Q + V258P + A276S + N355G + 58.0 H358D + A364G + S388K + D470T + L530R V45L + A117S + L149R + S214Q + V258P + A276S + V350L + 58.0 H358D + A364G + S388K + D470T + L530R V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 58.0 A364G + S388K + D470T + S481S + L530R V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 58.0 A364G + S388K + D470T + Q496E + L530R V45L + A117S + L149R + N168G + S214Q + V258P + A276S + 58.0 H358D + A364G + S388K + D470T + L530R V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 58.0 A364G + S388K + D470T + V498I + L530R V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 58.0 A364G + S388K + D470A + R483V V45N + A117S + L149R + S214Q + V258P + A276S + H358D + 58.0 A364G + S388K + D470T + R483V V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 58.0 A364G + S388K + D470T + R483V + A499Y V45L + A79C + L149R + V258P + A276S + Q314A + A364G + 58.0 S388K V45L + A79C + L149R + V258P + A276S + L281V + A364G + 58.0 S388K V45L + A117S + L149R + S214Q + V258P + A276S + A286S + 57.9 H358D + A364G + S388K + D470T + L530R V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 57.9 A364G + S388K + D470T + S501N + L530R V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 57.9 A364G + S388K + D470T + N476N + L530R V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 57.9 A364G + S388K + D470T + T477V + L530R V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 57.9 A364G + S388H + D470T + L530R V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 57.9 A364G + S388K + D470T + L478N + L530R V45L + S92D + A117S + L149R + S214Q + V258P + A276S + 57.9 H358D + A364G + S388K + D470T + L530R V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 57.9 A364G + S388K + D470T + V500V + L530R V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 57.9 A364G + S388K + D470T + R483V + V500V V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 57.9 A364G + S388K + D470T + L478P + L530R V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 57.9 A364G + S388K + D470T + R483V + S501E V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 57.9 A364G + S388K + D470T + D525L + L530R V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 57.9 A364G + S388K + D470T + G526T + L530R V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 57.9 A364G + S388K + D470T + N527H + L530R V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 57.9 A364G + S388K + D470T + T477K + L530R M28P + V45L + A117S + L149R + S214Q + V258P + A276S + 57.9 H358D + A364G + S388K + D470T + L530R D9E + V45L + A117S + L149R + S214Q + V258P + A276S + 57.9 H358D + A364G + S388K + D470T + R483V V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 57.8 A364G + S388K + D470T + S501E + L530R V45L + A117S + L149R + S214Q + W250Y + V258P + A276S + 57.8 H358D + A364G + S388K + D470T + L530R V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 57.8 A364G + S388K + D470T + A499L + L530R V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 57.8 A364G + S388K + D470T + A472I + L530R V45L + A117S + N127D + L149R + S214Q + V258P + A276S + 57.8 H358D + A364G + S388K + D470T + R483V V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 57.7 A364G + S388K + D470T + V500T + L530R V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 57.7 A364G + S388K + D470T + R483V + N527H V45N + A117S + L149R + S214Q + V258P + A276S + H358D + 57.7 A364G + S388K + D470T + L530R V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 57.7 A364G + S388K + D470T + T480N + L530R V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 57.7 A364G + S388K + D470T + R483V + V497P V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 57.7 A364G + S388K + D470T + R483V + V498I V45L + A79C + L149R + S173Y + V258P + A276S + A364G + 57.7 S388K V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 57.7 A364G + S388K + D470T + T480N + R483V V45L + A117S + L149R + S214Q + H219V + V258P + A276S + 57.6 H358D + A364G + S388K + D470T + L530R V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 57.6 A364G + S388A + D470T + L530R M28P + V45L + A117S + L149R + S214Q + V258P + A276S + 57.6 H358D + A364G + S388K + D470T + R483V V45L + A117S + L149R + A170S + S214Q + V258P + A276S + 57.6 H358D + A364G + S388K + D470T + R483V V45L + A79C + L149R + G187K + V258P + A276S + A364G + 57.6 S388K V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 57.6 A364G + S388K + S389H + D470T + L530R V45L + D113T + A117S + L149R + S214Q + V258P + A276S + 57.5 H358D + A364G + S388K + D470T + L530R V45L + A117S + L149R + N163H + S214Q + V258P + A276S + 57.5 H358D + A364G + S388K + D470T + R483V V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 57.5 A364G + S388A + D470T + R483V V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 57.5 A364G + S388L + D470T + R483V V45L + Q61R + A79C + L149R + V258P + A276S + A364G + 57.5 S388K V45L + A79C + L149R + N168G + V258P + A276S + A364G + 57.5 S388K V45L + A117S + L149R + T211H + S214Q + V258P + A276S + 57.5 H358D + A364G + S388K + D470T + L530R V45L + A79C + L149R + T215V + V258P + A276S + A364G + 57.4 S388K V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 57.4 A364G + S388K + D470T + R483V + V500T V45L + A79C + L149R + V258P + A276S + A286S + A364G + 57.3 S388K V45L + A79C + L149R + H219V + V258P + A276S + A364G + 57.3 S388K V45L + A79C + L149R + A170S + V258P + A276S + A364G + 57.3 S388K V45L + D113T + A117S + L149R + S214Q + V258P + A276S + 57.3 H358D + A364G + S388K + D470T + R483V V45L + Q61K + A117S + L149R + S214Q + V258P + A276S + 57.3 H358D + A364G + S388K + D470T V45L + D95N + A117S + L149R + S214Q + V258P + A276S + 57.3 H358D + A364G + S388K + G394A + D470T V45L + A79C + L149R + V258P + A276S + A364G + S388K 57.2 V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 57.2 S388K + G394A + D470T + R483V V45L + A93T + A117S + L149R + S214Q + V258P + A276S + 57.2 H358D + A364G + S388K + D470T + A499Y V45L + A117S + L149R + S214Q + T215I + V258P + A276S + 57.2 H358D + A364G + S388K + D470T + R483V V45L + A117S + L149R + S214Q + H219I + V258P + A276S + 57.2 H358D + A364G + S388K + D470T + R483V V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 57.2 A364G + S388K + D470T + L478N V45L + A117S + L149R + S214Q + V258P + A276S + L281V + 57.2 H358D + A364G + S388K + D470T V45L + A117S + L149R + S214E + V258P + A276S + H358D + 57.2 A364G + S388K + D470T V45L + T70R + A117S + L149R + S214Q + V258P + A276S + 57.2 L281V + H358D + A364G + S388K + G394A + C468L + D470T + R483V V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 57.2 A364G + Q385C + S388K + D470T + L530R V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 57.1 A364G + T366I + S388K + D470T V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 57.1 A364G + S388K + D470T + S473G V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 57.1 A364G + S388K + D470T + L478P V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 57.1 A364G + S388K + G394D + D470T V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 57.1 Q384A + S388K + D470T + R483V D11E + V45L + A79C + L149R + V258P + A276S + A364G + 57.1 S388K V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 57.1 A364G + S388K + D470T + R483V + L530R V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 57.1 A364G + S388K + D470T + N529T V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 57.1 A364G + S388K + G394Q + D470T V45L + A117S + L149R + G187L + S214Q + V258P + A276S + 57.1 H358D + A364G + S388K + D470T V45L + A79C + L149R + V258P + A276S + A286E + A364G + 57.0 S388K V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 57.0 A364G + S388K + D470T + R483V + G503L V45L + A117S + L149R + S214Q + V258P + A276S + Q314A + 57.0 H358D + A364G + S388K + D470T V45L + A117S + L149R + S214Q + V258P + A276S + V350L + 57.0 H358D + A364G + S388K + D470T V45L + A117S + L149R + G187K + S214Q + V258P + A276S + 57.0 H358D + A364G + S388K + D470T V45L + A117S + L149R + S214Q + W250Y + V258P + A276S + 57.0 H358D + A364G + S388K + D470T V45L + A117S + L149R + S214Q + V258P + A276S + A286E + 57.0 H358D + A364G + S388K + D470T V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 57.0 A364G + Q384A + S388K + D470T V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 57.0 A364G + S388R + D470T V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 57.0 A364G + S388K + D470T + S528H V45L + A117S + L149R + S214Q + T215V + V258P + A276S + 56.9 H358D + A364G + S388K + D470T + R483V V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 56.9 A364G + S388K + D470T + Q496R V45L + A117S + L149R + N163H + S214Q + V258P + A276S + 56.9 H358D + A364G + S388K + D470T V45L + A117S + L149R + S214Q + V258P + A276S + S282N + 56.9 H358D + A364G + S388K + D470T V45L + A117S + L149R + S214Q + V258P + A276Q + H358D + 56.9 A364G + S388K + D470T D11E + V45L + A117S + L149R + S214Q + V258P + A276S + 56.9 H358D + A364G + S388K + D470T V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 56.9 A364G + T366V + S388K + D470T V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 56.9 A364G + S388K + D470T + S473K V45L + A79C + L149R + T180Q + V258P + A276S + A364G + 56.9 S388K V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 56.9 A364G + S388K + D470T + S481A + R483V V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 56.9 A364G + S388R + D470T + R483V V45L + A117S + L149R + S214Q + V258P + A276S + Q314A + 56.9 A364G + S388K + D470T + R483V V45L + S92D + A117S + L149R + S214Q + V258P + A276S + 56.9 H358D + A364G + S388K + D470T V45L + A117S + L149R + S214Q + V258P + N260H + A276S + 56.9 H358D + A364G + S388K + D470T V45L + A117S + L149R + G187S + S214Q + V258P + A276S + 56.9 H358D + A364G + S388K + D470T V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 56.9 A364G + S388K + D470T + T477K V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 56.9 A364G + S388K + D470T + N474G V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 56.9 A364G + S388K + N395D + D470T V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 56.8 A364G + S388K + D470T + S501N V45L + A117S + N127D + L149R + S214Q + V258P + A276S + 56.8 H358D + A364G + S388K + D470T V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 56.8 A364G + S388K + V393R + D470T V45L + A117S + L149R + S173Y + S214Q + V258P + A276S + 56.8 H358D + A364G + S388K + D470T V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 56.8 A364G + S388H + D470T V45L + A117S + L149R + S214Q + T215V + V258P + A276S + 56.8 H358D + A364G + S388K + D470T + L530R V45L + A117S + L149R + G187S + S214Q + V258P + A276S + 56.8 H358D + A364G + S388K + D470T + L530R V45L + A117S + L149R + T211H + S214Q + V258P + A276S + 56.8 H358D + A364G + S388K + D470T + R483V V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 56.7 A364G + S388K + D470T + T480N V45L + A117S + L149R + N168G + S214Q + V258P + A276S + 56.7 H358D + A364G + S388K + D470T V45L + A79C + L149R + H219I + V258P + A276S + A364G + 56.7 S388K V45L + L149R + S214E + V258P + A276S + H358D + A364G + 56.7 D470T V45L + Q61K + A117S + L149R + S214Q + V258P + A276S + 56.7 A364G + S388K + D470T + R483V V45L + D113T + A117S + L149R + S214Q + V258P + A276S + 56.7 H358D + A364G + S388K + D470T V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 56.7 T366V + S388K + D470T + R483V V45L + A117S + L149R + S214Q + V258P + A276S + H358T + 56.7 A364G + S388K + D470T + R483V V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 56.7 S388K + V393R + D470T + R483V V45N + A79C + L149R + V258P + A276S + A364G + S388K 56.7 V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 56.6 A364G + S388K + D470T + Q496Q V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 56.6 S388K + G394Q + D470T + R483V V45L + A79C + L149R + V258P + A276S + V350L + A364G + 56.6 S388K V45L + L149R + S214E + V258P + A276S + H358D + A364G + 56.6 D470T V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 56.6 T366I + S388K + D470T + R483V V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 56.6 A364G + S388K + D470T + R483V + G526T V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 56.6 A364G + S388K + D470T + L484S V45L + A79C + A117S + L149R + S214Q + V258P + A276S + 56.6 H358D + A364G + S388K V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 56.6 A364G + S388K + D470T + A499L V45L + A117S + L149R + S214Q + V258P + A276S + H358T + 56.6 A364G + S388K + D470T + L530R V45L + A79C + D113T + L149R + V258P + A276S + A364G + 56.5 S388K V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 56.5 A364G + S388K + D470T + R483V + D525L V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 56.5 A364G + S388K + D470T + V498I V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 56.5 A364G + S388L + D470T V45L + T70R + A117S + L149R + S214Q + V258P + A276S + 56.5 A364G + S388K + D470T + R483V V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 56.5 A364G + S388K + D470T + S528H + L530R V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 56.5 S388K + D470T + N476D + R483V D9E + V45L + A117S + L149R + S214Q + V258P + A276S + 56.5 A364G + S388K + D470T + R483V V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 56.4 A364G + S388K + D470T + S501E V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 56.4 A364G + S388K + D470T + S481A V45L + A117S + L149R + S214Q + H219V + V258P + A276S + 56.4 H358D + A364G + S388K + D470T V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 56.4 A364G + S388K + D470T + S481S V45L + A117S + L149R + G187K + S214Q + V258P + A276S + 56.4 A364G + S388K + D470T + R483V V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 56.4 S388K + N395D + D470T + R483V V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 56.4 A364G + S388K + I469T + D470T + R483V V45L + A79C + N127D + L149R + V258P + A276S + A364G + 56.4 S388K D9E + V45L + A79C + L149R + V258P + A276S + A364G + 56.4 S388K V45L + L149R + S214E + V258P + A276S + H358D + A364G + 56.4 D470T V45L + A117S + L149R + G187L + S214Q + V258P + A276S + 56.4 A364G + S388K + D470T + R483V V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 56.4 A364G + S388K + D470T + N529T + L530R V45L + A79C + L149R + W250Y + V258P + A276S + A364G + 56.4 S388K V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 56.4 A364G + S388K + D470T + V497P V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 56.4 A364G + S388K + D470T + N527H V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 56.4 S388K + D470T + R483V + Q496Q V45L + A117S + L149R + N168G + S214Q + V258P + A276S + 56.4 A364G + S388K + D470T + R483V V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 56.4 S388K + D470T + N476N + R483V V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 56.3 S388K + D470T + T477V + R483V V45L + A117S + L149R + S214Q + V258P + A276S + V350L + 56.3 A364G + S388K + D470T + R483V V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 56.3 S388K + D470T + L478N + R483V V45L + A117S + L149R + S214E + V258P + A276S + A364G + 56.3 S388K + D470T + R483V M28P + V45L + A117S + L149R + S214Q + V258P + A276S + 56.3 H358D + A364G + S388K + D470T V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 56.3 S388K + V393H + D470T + R483V V45L + Q61R + A117S + L149R + S214Q + V258P + A276S + 56.3 A364G + S388K + D470T + R483V V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 56.3 S388K + D470T + R483V + V497P V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 56.3 S388K + D470T + R483V + V498I V45L + A117S + L149R + S214Q + V258P + A276S + S282N + 56.2 H358D + A364G + S388K + D470T + L530R V45L + T70R + A117S + L149R + S214Q + V258P + A276S + 56.2 L281V + H358D + A364G + C375V + S388K + G394A + D470T + R483V V45L + A117S + L149R + S214Q + V258P + A276S + A286E + 56.2 A364G + S388K + D470T + R483V V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 56.2 S388R + D470T + R483V V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 56.2 S388K + D470A + R483V V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 56.2 S388K + D470T + T477K + R483V V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 56.2 S388K + D470T + R483V + Q496E V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 56.2 S388K + D470T + R483V + Q496R V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 56.2 S388K + D470T + R483V + A499L V45L + L149R + S214E + V258P + A276S + H358D + A364G + 56.2 D470T V45L + L149R + S214E + V258P + A276S + H358D + A364G + 56.2 D470T V45L + A117S + L149R + S214Q + T215I + V258P + A276S + 56.2 H358D + A364G + S388K + D470T V45L + T70R + A117S + L149R + S214Q + V258P + A276S + 56.2 L281V + H358D + A364G + S388K + G394A + C468S + D470T + R483V V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 56.1 S388K + Y391V + D470T + R483V V45L + A117S + L149R + S214Q + V258P + A276Q + A364G + 56.1 S388K + D470T + R483V V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 56.1 A364G + S388K + D470T + G503L + L530R V45L + A117S + L149R + S214Q + H219I + V258P + A276S + 56.1 H358D + A364G + S388K + D470T + L530R V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 56.1 A364G + S388K + D470T + N476D V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 56.1 A364G + S388K + V393H + D470T V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 56.1 S388K + D470T + R483V V45L + A117S + L149R + S214Q + V258P + A276S + A286S + 56.1 A364G + S388K + D470T + R483V V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 56.1 S388K + D470T + R483V + S501E V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 56.1 S388K + D470T + R483V + N529T V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 56.1 S388K + D470T + R483V + S501N V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 56.1 A364G + S388K + D470T V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 56.1 S388K + D470T + S481S + R483V V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 56.1 S388K + D470T + L478P + R483V D11E + V45L + A117S + L149R + S214Q + V258P + A276S + 56.1 A364G + S388K + D470T + R483V V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 56.0 A364G + S388K + D470T + T477V V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 56.0 A364G + S388K + D470T + V497P + L530R V45L + A117S + L149R + T211H + S214Q + V258P + A276S + 56.0 H358D + A364G + S388K + D470T V45L + A117S + L149R + S214Y + V258P + A276S + H358D + 56.0 A364G + S388K + D470T + R483V V45L + A117S + L149R + S214Q + W250Y + V258P + A276S + 56.0 A364G + S388K + D470T + R483V V45L + S92D + A117S + L149R + S214Q + V258P + A276S + 56.0 A364G + S388K + D470T + R483V V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 56.0 S388K + D470T + R483V + N527H V45N + A117S + L149R + S214Q + V258P + A276S + A364G + 56.0 S388K + D470T + R483V V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 55.9 A364G + Q385C + S388K + D470T V45L + A117S + L149R + S173Y + S214Q + V258P + A276S + 55.9 A364G + S388K + D470T + R483V V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 55.9 S388H + D470T + R483V V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 55.9 S388K + S389H + D470T + R483V V45L + A117S + L149R + S214Q + H219V + V258P + A276S + 55.9 A364G + S388K + D470T + R483V V45L + A79C + A117S + L149R + S214Q + V258P + A276S + 55.9 A364G + S388K + D470T V45L + A117S + L149R + S214Q + T215I + V258P + A276S + 55.9 H358D + A364G + S388K + D470T + L530R V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 55.9 A364G + S388K + D470T + Q496E V45L + A117S + L149R + A170S + S214Q + V258P + A276S + 55.9 H358D + A364G + S388K + D470T V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 55.8 A364G + S388K + S389V + D470T + R483V V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 55.8 A364G + S388K + S389V + D470T + L530R V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 55.8 A364G + S388A + D470T V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 55.8 A364G + S388K + S389V + D470T V45L + T70R + A117S + L149R + S214Q + V258P + A276S + 55.8 H358D + A364G + S388K + D470T V45L + A117S + L149R + S214Q + H219I + V258P + A276S + 55.8 A364G + S388K + D470T + R483V V45L + A79C + L149R + N163H + V258P + A276S + A364G + 55.7 S388K V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 55.7 S388K + D470T + R483V + A499Y V45L + A117S + L149R + S214Q + V258P + A276S + L281V + 55.7 A364G + S388K + D470T + R483V V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 55.6 S388K + D470T + R483V + V500T V45L + A117S + L149R + T180Q + S214Q + V258P + A276S + 55.6 H358D + A364G + S388K + D470T V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 55.6 A364G + S388K + D470T + V500V V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 55.6 A364G + S388K + D470T + G526T V45L + C60L + T70R + A117S + L149R + S214Q + V258P + 55.6 A276S + L281V + H358D + A364G + S388K + G394A + D470T + R483V V45L + C69L + T70R + A117S + L149R + S214Q + V258P + 55.6 A276S + L281V + H358D + A364G + S388K + G394A + D470T + R483V V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 55.5 S388A + D470T + R483V V45L + A117S + L149R + S214Q + V258P + A276S + A286S + 55.5 H358D + A364G + S388K + D470T V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 55.4 A364G + S388K + D470T + R483V + V497D V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 55.4 A364G + S388K + D470A + L530R V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 55.4 S388K + D470T + R483V + D525L V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 55.4 A364G + S388K + D470T + N476N V45L + A117S + L149R + S214Q + V258P + A276S + L281V + 55.3 A364G + S388K + D470T V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 55.3 Q384A + S388K + D470T V45L + A117S + L149R + S214Q + V258P + A276S + A286E + 55.3 A364G + S388K + D470T V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 55.2 S388K + D470T + T477K V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 55.1 A364G + S388K + S389H + D470T V45L + A117S + L149R + S214Y + V258P + A276S + H358D + 55.1 A364G + S388K + D470T + L530R V45L + A117S + L149R + S214Y + V258P + A276S + H358D + 55.1 A364G + S388K + D470T V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 55.1 S388K + G394A + D470T V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 55.1 S388K + D470T + N476D V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 55.0 A364G + S388K + D470T + L478N + R483V V45L + C60A + T70R + A117S + L149R + S214Q + V258P + 55.0 A276S + L281V + H358D + A364G + S388K + G394A + D470T + R483V V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 55.0 S388K + V393H + D470T V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 55.0 S388K + N395D + D470T A25W + V45L + A117S + L149R + S214Q + V258P + A276S + 55.0 H358D + A364G + S388K + D470T V45L + T70R + A117S + L149R + S214Q + C243L + V258P + 55.0 A276S + L281V + H358D + A364G + S388K + G394A + D470T + R483V V45L + A117S + L149R + S214Q + V258P + A276S + H358T + 55.0 A364G + S388K + D470T V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 54.9 S388K + D470T + L478N V45L + C60S + T70R + A117S + L149R + S214Q + V258P + 54.9 A276S + L281V + H358D + A364G + S388K + G394A + D470T + R483V V45L + A117S + L149R + S214Q + W250Y + V258P + A276S + 54.9 A364G + S388K + D470T V45L + A117S + L149R + S214Q + T215V + V258P + A276S + 54.9 A364G + S388K + D470T + R483V V45L + Q61R + A117S + L149R + S214Q + V258P + A276S + 54.8 H358D + A364G + S388K + D470T V45L + A117S + L149R + G187L + S214Q + V258P + A276S + 54.8 A364G + S388K + D470T D9E + V45L + A117S + L149R + S214Q + V258P + A276S + 54.8 A364G + S388K + D470T V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 54.8 A364G V45L + C69A + T70R + A117S + L149R + S214Q + V258P + 54.8 A276S + L281V + H358D + A364G + S388K + G394A + D470T + R483V V45L + T70R + A117S + L149R + C161S + S214Q + V258P + 54.8 A276S + L281V + H358D + A364G + S388K + G394A + D470T + R483V V45L + A117S + L149R + S214Q + H219I + V258P + A276S + 54.8 H358D + A364G + S388K + D470T V45L + A117S + L149R + S214Q + V258P + A276S + S282N + 54.8 A364G + S388K + D470T V45L + A117S + L149R + T211H + S214Q + V258P + A276S + 54.7 A364G + S388K + D470T + R483V V45L + D95N + A117S + L149R + S214Q + V258P + A276S + 54.7 H358D + A364G + S388K + S473G V45L + T70R + D95N + A117S + L149R + S214Q + V258P + 54.7 A276S + L356M + H358D + A364G + S388K D11E + V45L + A117S + L149R + S214Q + V258P + A276S + 54.7 A364G + S388K + D470T V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 54.7 S388K + D470T + N476N V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 54.7 S388K + G394D + D470T V45L + Q61K + A117S + L149R + S214Q + V258P + A276S + 54.7 A364G + S388K + D470T V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 54.7 A364G + S388K + D470T + G503L V45L + A117S + L149R + S214Q + V258P + A276S + A286S + 54.7 A364G + S388K + D470T V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 54.6 A364G + S388K + D470A V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 54.6 S388K + G394Q + D470T V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 54.6 S388R + D470T V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 54.6 S388K + D470T + L478P V45L + A117S + L149R + S214Q + V258P + A276S + V350L + 54.6 A364G + S388K + D470T V45L + D113T + A117S + L149R + S214Q + V258P + A276S + 54.6 A364G + S388K + D470T V45L + A117S + L149R + T180Q + S214Q + V258P + A276S + 54.6 A364G + S388K + D470T V45L + C69V + T70R + A117S + L149R + S214Q + V258P + 54.6 A276S + L281V + H358D + A364G + S388K + G394A + D470T + R483V V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 54.6 A364G + S388K + D470T + D525L V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 54.5 S388K + D470T V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 54.5 A364G + S388K + D470T + V500T V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 54.4 S388K + S389H + D470T V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 54.4 S388K + V393R + D470T V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 54.4 S388K + D470T + Q496R V45L + A117S + N127D + L149R + S214Q + V258P + A276S + 54.4 A364G + S388K + D470T V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 54.4 S388K + D470T + A499Y V45L + A117S + L149R + S214Q + T215V + V258P + A276S + 54.4 H358D + A364G + S388K + D470T V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 54.4 A364G + S388K + D470T + T480L V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 54.4 S388L + D470T V45L + A117S + L149R + S173Y + S214Q + V258P + A276S + 54.4 A364G + S388K + D470T V45L + S92D + A117S + L149R + S214Q + V258P + A276S + 54.4 A364G + S388K + D470T V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 54.4 S388K + S389V + D470T + R483V V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 54.4 S388K + D470T + N529T V45L + C60V + T70R + A117S + L149R + S214Q + V258P + 54.3 A276S + L281V + H358D + A364G + S388K + G394A + D470T + R483V V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 54.3 S388K + D470T + R483V + V497E V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 54.3 A364G + S388K + L478N V45L + T70R + A117S + L149R + S214Q + V258P + A276S + 54.3 A364G + S388K + D470T M28P + V45L + A117S + L149R + S214Q + V258P + A276S + 54.3 A364G + S388K + D470T V45L + A117S + L149R + S214Q + V258P + A276Q + A364G + 54.3 S388K + D470T V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 54.3 A364G + S388K + D470V + R483V V45L + A117S + L149R + S214Y + V258P + A276S + A364G + 54.3 S388K + D470T + R483V V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 54.3 A364G + S388K + N395D V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 54.3 A364G + S388K + T477K V45L + A117S + L149R + S214Q + V258P + A276S + L281V + 54.3 H358D + A364G + S388K V45L + Q61R + A117S + L149R + S214Q + V258P + A276S + 54.2 A364G + S388K + D470T V45L + A117S + L149R + S214Q + T215I + V258P + A276S + 54.2 A364G + S388K + D470T V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 54.2 S388K + D470T + Q496E V45L + A117S + L149R + G187K + S214Q + V258P + A276S + 54.2 A364G + S388K + D470T V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 54.2 S388K + D470T + W495I V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 54.2 S388K + D470T + V498I V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 54.2 A364G + S388K + D470K + R483V V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 54.2 S388K + D470T + V500V D11E + V45L + A117S + L149R + S214Q + V258P + A276S + 54.2 H358D + A364G + S388K V45L + A117S + L149R + A170S + S214Q + V258P + A276S + 54.2 A364G + S388K + D470T V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 54.2 S388K + Y391V + D470T V45L + A117S + L149R + S214Q + V258P + A276S + Q314A + 54.2 A364G + S388K + D470T V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 54.2 S388K + D470T + T477V A25W + V45L + A79C + L149R + S214E + V258P + A276S + 54.2 A364G V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 54.1 A364G + S388K + G394Q V45L + A117S + L149R + S214Q + H219V + V258P + A276S + 54.1 A364G + S388K + D470T V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 54.1 S388K + D470T + Q496Q V45L + T70R + A117S + L149R + S214Q + V258P + A276S + 54.1 L281V + H358D + A364G + C375A + S388K + G394A + D470T + R483V V45L + A117S + L149R + D192E + S214Q + V258P + A276S + 54.1 H358D + A364G V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 54.1 A364G + S388K + D470T + A472L V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 54.1 A364G + S388K + A499Y V45L + A117S + L149R + S214Q + T215V + V258P + A276S + 54.0 A364G + S388K + D470T V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 54.0 Q385C + S388K + D470T V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 54.0 S388A + D470T V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 54.0 S388H + D470T V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 54.0 S388K + D470T + T480N V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 54.0 S388K + D470T + V497P V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 54.0 S388K + D470T + A499L V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 54.0 S388K + D470T + S501N V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 54.0 D470T V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 54.0 A364G + Q384A + S388K V45L + T70R + A117S + L149R + S214Q + V258P + A276S + 54.0 L281V + H358D + A364G + C375S + S388K + G394A + D470T + R483V V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 53.9 S388L + D470T + R483V V45L + A79C + S92D + L149R + V258P + A276S + A364G + 53.9 S388K V45L + T70R + A117S + L149R + S214Q + V258P + A276S + 53.9 L281V + H358D + A364G + S388K + G394A + D470T + R483V + C540A V45N + A117S + L149R + S214Q + V258P + A276S + A364G + 53.9 S388K + D470T V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 53.9 A364G + S388K + G394A V45L + C69S + T70R + A117S + L149R + S214Q + V258P + 53.8 A276S + L281V + H358D + A364G + S388K + G394A + D470T + R483V V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 53.8 A364G + S388K + V498I V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 53.8 A364G V45L + A117S + L149R + S214Q + H219I + V258P + A276S + 53.8 A364G + S388K + D470T V45L + A117S + L149R + N163H + S214Q + V258P + A276S + 53.7 A364G + S388K + D470T V45L + L149R + S214Q + V258P + A276S + H358D + A364G 53.7 V45L + A117S + L149R + S214Q + V258P + A276S + Q314A + 53.7 H358D + A364G + S388K V45L + A117S + L149R + S173Y + S214Q + V258P + A276S + 53.7 H358D + A364G + S388K V45L + A117S + L149R + S214E + V258P + A276S + H358D + 53.7 A364G + S388K V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 53.7 A364G + S388K + G394D A25W + V45L + A79C + L149R + V258P + A276S + A364G 53.6 V45L + L149R + S214Q + V258P + A276S + A286E + A364G + 53.6 S388K V45L + Q61R + A117S + L149R + S214Q + V258P + A276S + 53.6 H358D + A364G + S388K V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 53.6 A364G + T366V + S388K V45L + A117S + L149R + D192E + S214Q + V258P + A276S + 53.6 H358D + A364G V45L + A117S + L149R + T180Q + S214Q + V258P + A276S + 53.5 H358D + A364G + S388K V45L + A117S + L149R + S214Q + T215I + V258P + A276S + 53.5 H358D + A364G + S388K V45L + A117S + L149R + S214Q + W250Y + V258P + A276S + 53.5 H358D + A364G + S388K V45L + L149R + S214Q + T215I + V258P + A276S + A364G + 53.5 S388K V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 53.5 A364G + S388K + N476D V45L + D113T + A117S + L149R + S214Q + V258P + A276S + 53.5 A364G + S388K + D470T + R483V V45L + A117S + L149R + S214Q + T215K + V258P + A276S + 53.4 A364G + S388K + D470T + R483V V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 53.4 A364G + S388K V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 53.4 A364G + S388K + T477V V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 53.4 A364G + S388K + L478P V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 53.4 A364G + S388K + S481A A25W + V45L + L149R + S214Q + V258P + A276S + A364G + 53.4 S388K V45L + A117S + L149R + T211H + S214Q + V258P + A276S + 53.4 A364G + S388K + D470T V45L + A117S + L149R + S214Q + T215K + V258P + A276S + 53.4 H358D + A364G + S388K + D470T + R483V V45L + A79C + L149R + V258P + A276S + L281V + A364G 53.4 V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 53.4 S388K + R483V V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 53.4 A364G + S388K + V500T V45L + A117S + L149R + S214Q + V258P + A276S + V350L + 53.3 H358D + A364G + S388K V45L + A117S + L149R + G187K + S214Q + V258P + A276S + 53.3 H358D + A364G + S388K V45L + T70R + A117S + L149R + S214Q + V258P + A276S + 53.3 L281V + H358D + A364G + C375L + S388K + G394A + D470T + R483V V45L + L149R + A170S + S214Q + V258P + A276S + A364G + 53.3 S388K V45L + A117S + L149R + S214E + V258P + A276S + A364G + 53.3 S388K + D470T V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 53.3 S388K + D470V + R483V V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 53.3 A364G + S388K + V500V V45L + Q61K + L149R + S214Q + V258P + A276S + A364G + 53.3 S388K V45L + L149R + N168G + S214Q + V258P + A276S + A364G + 53.3 S388K V45L + A117S + L149R + N163H + S214Q + V258P + A276S + 53.3 H358D + A364G + S388K V45L + A79C + D95D + L149R + V258P + A276S + A364G + 53.3 S388K V45L + Q77E + A79C + L149R + V258P + A276S + A364G + 53.3 S388K V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 53.2 S388K + D470T + R483V + V497W V45L + L149R + S214Q + V258P + A276S + S282N + A364G + 53.2 S388K V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 53.2 A364G + S388R V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 53.2 A364G + S388K + S481S V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 53.2 S388K + D470T + V500T V45L + T70R + A117S + L149R + S214Q + V258P + A276S + 53.2 L281V + H358D + A364G + S388K + G394A + D470T + R483V + C540L V45L + T70R + A117S + L149R + S214Q + V258P + A276S + 53.2 L281V + H358D + A364G + S388K + G394A + D470T + R483V + C522S V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 53.2 A364G + S388K + W495S V45L + L149R + S214Q + V258P + A276S + Q314A + A364G + 53.2 S388K V45L + D113T + A117S + L149R + S214Q + V258P + A276S + 53.2 H358D + A364G + S388K V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 53.1 A364G + S388K + D470T + R483V + V497W V45L + T70R + A117S + L149R + S214Q + V258P + A276S + 53.1 L281V + H358D + A364G + S388K + G394A + D470T + R483V + C540S V45L + T70R + A117S + L149R + S214Q + V258P + A276S + 53.1 L281V + H358D + A364G + S388K + G394A + C396S + D470T + R483V V45L + T70R + L149R + S214Q + V258P + A276S + A364G + 53.1 S388K V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 53.1 A364G + S388K + N474G V45L + A117S + L149R + S214Q + V258P + A276S + S282N + 53.1 H358D + A364G + S388K V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 53.1 A364G + S388K + Q496Q V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 53.1 S388K + S389V + D470T V45L + T70R + A117S + L149R + S214Q + V258P + A276S + 53.0 L281V + H358D + A364G + S388K + G394A + C396A + D470T + R483V V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 53.0 A364G + S388K + S501E A25W + V45L + L149R + S214E + V258P + A276S + A364G 53.0 V45L + L149R + S214Q + W250Y + V258P + A276S + A364G + 53.0 S388K V45L + L149R + G187K + S214Q + V258P + A276S + A364G + 53.0 S388K V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 53.0 A364G + S388K + N476N V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 53.0 A364G + S388K + S473K V45L + A117S + L149R + G187L + S214Q + V258P + A276S + 53.0 H358D + A364G + S388K C40L + V45L + T70R + A117S + L149R + S214Q + V258P + 53.0 A276S + L281V + H358D + A364G + S388K + G394A + D470T + R483V V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 53.0 A364G + S388K + Q496E A25W + V45L + A117S + L149R + S214Q + V258P + A276S + 53.0 H358D + A364G + S388K V45L + L149R + V258P + A276S + L281V + H358T + A364G + 53.0 S388K V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 53.0 A364G + S388A V45L + A117S + L149R + N168G + S214Q + V258P + A276S + 53.0 H358D + A364G + S388K V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 53.0 A364G + S388K + S389H M28P + V45L + L149R + S214Q + V258P + A276S + A364G + 53.0 S388K V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 52.9 S388K + D470T + T480L V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 52.9 Q384A + S388K V45L + A93S + L149R + A252S + H334D 52.9 C40A + V45L + T70R + A117S + L149R + S214Q + V258P + 52.9 A276S + L281V + H358D + A364G + S388K + G394A + D470T + R483V V45L + L149R + G187L + S214Q + V258P + A276S + A364G + 52.9 S388K V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 52.9 A364G + Q385C + S388K V45L + L149R + S214Q + V258P + A276S + A286S + A364G + 52.9 S388K V45L + S92D + A117S + L149R + S214Q + V258P + A276S + 52.9 H358D + A364G + S388K V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 52.9 A364G + S388L V45L + A117S + L149R + S214Q + V258P + A276S + A286E + 52.8 A364G + S388K D9E + V45L + L149R + S214Q + V258P + A276S + A364G + 52.8 S388K V45L + L149R + S173Y + S214Q + V258P + A276S + A364G + 52.8 S388K V45L + A117S + L149R + A170S + S214Q + V258P + A276S + 52.8 H358D + A364G + S388K V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 52.8 A364G + S388K + Y391V V45L + A117S + L149R + S214Q + V258P + A276S + L281V + 52.8 A364G + S388K V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 52.8 S388K + G394D V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 52.8 S388K + S473G V45L + A79C + L149R + V258P + A276S + H358T + A364G + 52.8 S388K V45L + L149R + S214Q + V258P + A276Q + A364G + S388K 52.8 A25W + V45L + L149R + S214E + V258P + A276S + H358T + 52.7 A364G V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 52.7 A364G + S388K + T480N D9E + V45L + A117S + L149R + S214Q + V258P + A276S + 52.7 H358D + A364G + S388K V45L + A117S + L149R + S214Q + H219I + V258P + A276S + 52.7 H358D + A364G + S388K C40S + V45L + T70R + A117S + L149R + S214Q + V258P + 52.7 A276S + L281V + H358D + A364G + S388K + G394A + D470T + R483V C40V + V45L + T70R + A117S + L149R + S214Q + V258P + 52.7 A276S + L281V + H358D + A364G + S388K + G394A + D470T + R483V A25W + V45L + L149R + S214E + V258P + A276S + A286E + 52.7 A364G V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 52.7 S388K + G394A V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 52.7 A364G + S388K + A499L A25W + V45L + Q61K + L149R + S214E + V258P + A276S + 52.6 A364G V45L + A117S + L149R + S214Q + T215V + V258P + A276S + 52.6 H358D + A364G + S388K A25W + V45L + L149R + V258P + A276S + H358T + A364G + 52.6 S388K V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 52.6 S388K + D470T + R483V + W495E A25W + V45L + A79C + L149R + V258P + A276S 52.6 V45L + L149R + S214Q + V258P + A276S + V350L + A364G + 52.6 S388K D11E + V45L + L149R + S214Q + V258P + A276S + A364G + 52.6 S388K V45L + L149R + H219I + V258P + A276S + H358T + A364G + 52.5 S388K V45L + T70R + A117S + L149R + S214Q + V258P + A276S + 52.5 L281V + H358D + A364G + S388K + G394A + C396V + D470T + R483V V45N + L149R + S214Q + V258P + A276S + A364G + S388K 52.5 V45L + A117S + L149R + S214Q + H219V + V258P + A276S + 52.5 H358D + A364G + S388K V45N + A117S + L149R + S214Q + V258P + A276S + H358D + 52.5 A364G + S388K V45L + S92D + L149R + S214Q + V258P + A276S + A364G + 52.5 S388K V45L + L149R + V258P + A276S + H358T + A364G 52.5 V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 52.5 S388K + L478P V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 52.5 S388K + S481A V45L + A117S + L149R + S214Q + V258P + A276S + Q314A + 52.5 A364G + S388K A25W + V45L + L149R + T211H + S214E + V258P + A276S + 52.4 A364G A25W + V45L + L149R + S214E + H219V + V258P + A276S + 52.4 A364G V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 52.4 A364G + S388K + S389V V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 52.4 A364G + S388K + V393H V45L + A117S + L149R + S214Q + V258P + A276Q + H358D + 52.4 A364G + S388K V45L + A117S + N127D + L149R + S214Q + V258P + A276S + 52.4 H358D + A364G + S388K V45L + L149R + W250Y + V258P + A276S + H358T + 52.4 A364G + S388K D9E + V45L + L149R + V258P + A276S + H358T + A364G + 52.4 S388K V45L + L149R + H219V + V258P + A276S + H358T + 52.4 A364G + S388K V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 52.4 A364G + S388K + A472L A25W + V45L + L149R + V258P + A276S + A364G 52.4 V45L + A117S + L149R + G187K + S214Q + V258P + A276S + 52.4 A364G + S388K V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 52.4 S388K + L478N V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 52.4 S388K + V393R V45L + A117S + L149R + S214E + V258P + A276S + A364G + 52.4 S388K V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 52.4 T366V + S388K V45L + A117S + L149R + S214Q + V258P + A276S + H358T + 52.4 A364G + S388K D11E + A25W + V45L + L149R + S214E + V258P + A276S + 52.4 A364G V45L + T70R + A117S + L149R + C161V + S214Q + V258P + 52.4 A276S + L281V + H358D + A364G + S388K + G394A + D470T + R483V V45L + A117S + L149R + T211H + S214Q + V258P + A276S + 52.4 H358D + A364G + S388K V45L + L149R + V258P + A276S + Q314A + H358T + A364G + 52.4 S388K D11E + V45L + A117S + L149R + S214Q + V258P + A276S + 52.3 A364G + S388K V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 52.3 S388K + G394Q V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 52.3 S388K + N395D V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 52.3 S388K + V393H V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 52.3 S388K + S501E V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 52.3 S388K + S528H V45L + T70R + A117S + L149R + S214Q + V258P + A276S + 52.3 H358D + A364G + S388K + D470T + L530R V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 52.3 S388L V45L + T70R + A117S + L149R + S214Q + V258P + A276S + 52.3 L281V + H358D + A364G + S388K + G394A + C396L + D470T + R483V V45L + L149R + T180Q + S214Q + V258P + A276S + A364G + 52.3 S388K V45L + D113T + L149R + S214Q + V258P + A276S + A364G + 52.3 S388K V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 52.3 A364G + S388K + T480L V45L + A93S + L149R + A252S + H334D 52.3 V45L + A93S + L149R + V234P + A252S 52.3 V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 52.3 A364G + S388H A25W + V45L + Q61R + L149R + S214E + V258P + A276S + 52.3 A364G V45L + A117S + L149R + S214Q + T215K + V258P + A276S + 52.3 H358D + A364G + S388K + D470T V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 52.3 S388K + S389H V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 52.3 T366I + S388K V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 52.3 S388K + N474G A25W + V45L + L149R + S214E + V258P + A276S + L281V + 52.3 A364G D9E + A25W + V45L + L149R + S214E + V258P + A276S + 52.3 A364G V45L + A117S + L149R + S214Q + T215K + V258P + A276S + 52.2 H358D + A364G + S388K + D470T + L530R V45L + A117S + L149R + S214Y + V258P + A276S + H358D + 52.2 A364G + S388K V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 52.2 A364G + S388K + V393R V45L + Q61R + L149R + V258P + A276S + H358T + A364G + 52.2 S388K V45L + L149R + S214Q + V258P + A276S + A364G + S388K 52.2 V45L + D113T + L149R + V258P + A276S + H358T + A364G + 52.2 S388K V45L + A117S + L149R + S214Q + V258P + A276S + A286S + 52.2 A364G + S388K V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 52.2 S388R V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 52.2 S388K + A499Y V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 52.2 S388K + V500V V45L + Q61R + L149R + S214Q + V258P + A276S + A364G + 52.2 S388K V45L + L149R + S214E + V258P + A276S + H358T + A364G 52.2 V45L + A117S + L149R + S214Q + V258P + A276Q + A364G + 52.2 S388K V45L + L149R + V258P + A276S + L281V + A364G 52.2 V45L + A117S + L149R + S214Q + W250Y + V258P + A276S + 52.1 A364G + S388K V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 52.1 S388K + T480N V45L + A117S + L149R + G187S + S214Q + V258P + A276S + 52.1 A364G + S388K A25W + V45L + A117S + L149R + S214Q + V258P + A276S + 52.1 A364G + S388K V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 52.1 S388K V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 52.1 S388K + N476N A25W + V45L + L149R + S214E + V258P + A276Q + A364G 52.1 V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 52.1 S388K + N476D V45L + L149R + S214Q + V258P + A276S + L281V + A364G 52.1 V45L + A93S + L149R + A252S + H334D + A340G 52.1 V45L + A93S + L149R + A252S + H334D 52.1 V45L + A93S + L149R + A252S + H334D 52.1 V45L + L149R + A252S + H334D 52.1 V45L + N127D + L149R + V258P + A276S + A364G + S388K 52.1 V45L + L149R + V258P + A276S + H358T + A364G + S388K 52.1 V45L + L149R + V258P + A276S + A364G + S388K 52.1 D9E + V45L + A117S + L149R + S214Q + V258P + A276S + 52.1 A364G + S388K V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 52.1 S388K + S481S V45L + L149R + N168G + V258P + A276S + A364G 52.1 V45L + L149R + T180Q + V258P + A276S + H358T + A364G + 52.0 S388K V45L + L149R + G187L + V258P + A276S + A364G + S388K 52.0 V45L + L149R + W250Y + V258P + A276S + A364G + S388K 52.0 V45L + L149R + V258P + A276S + A286E + A364G + S388K 52.0 V45L + L149R + V258P + A276S + S282N + A364G + S388K 52.0 A25W + V45L + L149R + V258P + A276S + A364G + S388K 52.0 V45L + L149R + S214Q + V258P + A276S + H358T + A364G 52.0 V45L + L149R + S173Y + V258P + A276S + A364G 52.0 V45L + A117S + L149R + S214Q + H219V + V258P + A276S + 52.0 A364G + S388K V45L + A93S + L149R + A252S + H334D 52.0 V45L + A93S + L149R + A252S + H334D + A340G 52.0 V45L + L149R + S190E + D446T + R459V 52.0 A25W + V45L + L149R + V258P + A276S + H358T 52.0 A25W + V45L + S92D + L149R + S214E + V258P + A276S + 52.0 A364G A25W + V45L + L149R + S214E + V258P + A276S + V350L + 52.0 A364G A25W + V45L + L149R + S214Q + V258P + A276S + A364G 52.0 V45L + L149R + N168G + V258P + A276S + A364G + S388K 52.0 V45L + A117S + L149R + V258P + A276S + A364G + S388K 52.0 A25W + V45L + L149R + V258P + A276S + H358T + A364G 52.0 V45L + L149R + V258P + N260H + A276S + A364G + S388K 52.0 V45L + L149R + T215I + V258P + A276S + A364G + S388K 52.0 A25W + V45L + L149R + V258P + A276Q + A364G 52.0 V45L + T70R + A117S + L149R + C161L + S214Q + V258P + 51.9 A276S + L281V + H358D + A364G + S388K + G394A + D470T +R483V A25W + V45L + L149R + S214E + V258P + A276S 51.9 V45L + A117S + L149R + S214Q + V258P + A276S + A286S + 51.9 H358D + A364G + S388K V45L + L149R + T211H + S214Q + V258P + A276S + A364G + 51.9 S388K V45L + Q61K + L149R + V258P + A276S + H358T + A364G 51.9 V45L + L149R + V258P + A276S + Q314A + H358T + A364G 51.9 V45L + L149R + T180Q + V258P + A276S + A364G + S388K 51.9 V45L + L149R + V258P + A276S + Q314A + A364G + S388K 51.9 A25W + V45L + L149R + V258P + A276S + A286S + A364G 51.9 V45L + L149R + S190E + D446T 51.9 V45L + L149R + V258P + A276S + A364G 51.9 V45L + L149R + A170S + V258P + A276S + A364G 51.9 V45L + L149R + V258P + A276Q + A364G 51.9 V45L + T70R + A117S + L149R + S214Q + V258P + A276S + 51.9 L281V + H358D + A364G + S388K + G394A + D470T + R483V +C522A V45L + L149R + H219I + V258P + A276S + H358T + A364G 51.8 V45L + L149R + V258P + A276S + V350L + A364G + S388K 51.8 D11E + V45L + L149R + V258P + A276S + A364G + S388K 51.8 V45L + D113T + L149R + V258P + A276S + A364G + S388K 51.8 V45L + L149R + G187K + V258P + A276S + A364G + S388K 51.8 M28P + V45L + L149R + V258P + A276S + A364G + S388K 51.8 V45L + Q61R + A117S + L149R + S214Q + V258P + A276S + 51.8 H358D + A364G + S388K + D470T + R483V A25W + V45L + L149R + S214Q + V258P + A276S 51.8 V45L + A117S + L149R + S214Q + T215I + V258P + A276S + 51.8 A364G + S388K A25W + V45L + L149R + V258P + A276S + S388K 51.8 A25W + V45L + L149R + S214E + H219I + V258P + A276S + 51.8 A364G V45L + A93S + L149R + V234P + A252S + H334D 51.8 V45L + L149R + T211H + V258P + A276S + H358T + A364G + 51.8 S388K A25W + V45L + A117S + L149R + S214E + V258P + A276S + 51.8 A364G V45L + L149R + S173Y + V258P + A276S + A364G + S388K 51.8 A25W + V45L + L149R + V258P + A276S + Q314A + A364G 51.8 V45L + L149R + G187L + V258P + A276S + H358T + A364G 51.8 V45L + L149R + T215V + V258P + A276S + H358T + A364G 51.8 V45L + T70R + L149R + V258P + A276S + A364G + S388K 51.8 V45L + N127D + L149R + V258P + A276S + A364G 51.8 V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 51.7 S388K + Q496R V45L + L149R + W250Y + V258P + A276S + A364G 51.7 V45L + L149R + V258P + A276S + V350L + H358T + A364G 51.7 D9E + V45L + L149R + V258P + A276S + H358T + A364G 51.7 V45L + L149R + T211H + V258P + A276S + H358T + A364G 51.7 A25W + V45L + L149R + W250Y + A276Q + A364G 51.7 V45L + L149R + V258P + A276S + L281V + A364G + S388K 51.7 V45L + L149R + V258P + A276S + S282N + H358T + A364G 51.7 V45L + L149R + T215I + V258P + A276S + H358T + A364G 51.7 A25W + V45L + L149R + S173Y + V258P + A276S + A364G 51.7 V45L + Q61K + L149R + V258P + A276S + A364G + S388K 51.7 V45L + L149R + T180Q + V258P + A276S + A364G 51.7 V45L + A117S + L149R + A170S + S214Q + V258P + A276S + 51.7 A364G + S388K V45L + Q61R + A117S + L149R + S214Q + V258P + A276S + 51.7 A364G + S388K A25W + V45L + L149R + S214E + T215V + V258P + A276S + 51.7 A364G V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 51.7 S388K + V497P V45L + L149R + V258P + A276S + Q314A + A364G 51.7 V45L + A117S + L149R + V258P + A276S + A364G 51.7 V45L + A117S + L149R + V258P + A276S + H358T + A364G + 51.7 S388K V45L + L149R + N168G + V258P + A276S + H358T + A364G + 51.7 S388K A25W + V45L + Q61K + L149R + V258P + A276S + A364G 51.6 V45L + L149R + S214E + V258P + A276S + L281V + A364G 51.6 V45N + L149R + V258P + A276S + A364G + S388K 51.6 V45L + L149R + V258P + A276S + A286E + H358T + A364G 51.6 D9E + V45L + L149R + V258P + A276S + A364G + S388K 51.6 V45L + S92D + L149R + V258P + A276S + A364G + S388K 51.6 V45L + A117S + L149R + T180Q + S214Q + V258P + A276S + 51.6 A364G + S388K V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 51.6 S388H V45L + A117S + L149R + S214Q + T215V + V258P + A276S + 51.6 A364G + S388K V45L + A117S + L149R + S214Q + V258P + A276S + V350L + 51.6 A364G + S388K A25W + V45L + L149R + S214E + T215I + V258P + A276S + 51.6 A364G V45L + N127D + L149R + V258P + A276S + H358T + A364G + 51.6 S388K A25W + V45L + L149R + V258P + A276S + A286E + A364G 51.6 V45L + L149R + N168G + V258P + A276S + L281V + A364G 51.6 V45L + Q61R + L149R + V258P + A276S + H358T + A364G 51.6 V45L + L149R + G187S + V258P + A276S + A364G + S388K 51.6 V45L + L149R + V258P + A276S + L281V + Q314A + A364G 51.6 V45L + L149R + V258P + A276S + L281V + H358T + A364G 51.6 V45L + L149R + A170S + V258P + A276S + H358T + A364G 51.6 V45L + L149R + A170S + V258P + A276S + A364G + S388K 51.6 V45L + L149R + T215V + V258P + A276S + A364G + S388K 51.6 V45L + L149R + V258P + A276Q + L281V + A364G 51.6 V45L + T70R + A117S + L149R + S214Q + C243S + V258P + 51.5 A276S + L281V + H358D + A364G + S388K + G394A + D470T +R483V V45L + T70R + A117S + L149R + S214Q + V258P + A276S + 51.5 L281V + H358D + A364G + S388K + G394A + D470T + R483V +C522V A25W + V45L + L149R + V258P + A276S + Q314A 51.5 V45L + L149R + V258P + A276Q + H358T + A364G + S388K 51.5 A25W + V45N + L149R + S214E + V258P + A276S + A364G 51.5 V45L + L149R + V258P + A276S + A286E + A364G 51.5 V45L + L149R + V258P + A276S + A286S + H358T + A364G 51.5 A25W + V45L + L149R + G187S + V258P + A276S + A364G 51.5 V45L + L149R + T180Q + V258P + A276S + L281V + A364G 51.5 A25W + V45L + L149R + A276Q + L281V + A364G 51.5 V45L + S92D + L149R + V258P + A276S + L281V + A364G 51.5 V45L + Q61R + L149R + V258P + A276S + L281V + A364G 51.5 V45L + L149R + A170S + V258P + A276S + L281V + A364G 51.5 D11E + A25W + V45L + L149R + V258P + A276S + A364G 51.5 A25W + V45L + Q61R + L149R + V258P + A276S + A364G 51.5 A25W + V45L + L149R + T215V + V258P + A276S + A364G 51.5 D9E + V45L + L149R + V258P + A276S + L281V + A364G 51.5 A25W + V45L + L149R + V258P + A276S + V350L + A364G 51.5 V45L + Q61K + A117S + L149R + S214Q + V258P + 51.5 A276S +A364G + S388K V45L + A117S + L149R + S214Q + V258P + A276S + 51.5 A364G +S388K + Y391V V45L + A117S + L149R + N168G + S214Q + V258P + 51.5 A276S +A364G + S388K V45L + D113T + A117S + L149R + S214Q + V258P + 51.5 A276S +A364G + S388K A25W + V45L + L149R + V258P + A276S + A286E 51.5 A25W + V45L + L149R + V258P + A276S + L281V 51.5 A25W + V45L + D113T + L149R + V258P + A276S 51.5 V45L + L149R + H219V + V258P + A276S + L281V + A364G 51.5 V45L + L149R + T180Q + V258P + A276S + H358T + A364G 51.5 V45L + L149R + T215V + V258P + A276S + L281V + A364G 51.5 A25W + V45L + L149R + V258P + A276S + S282N + A364G 51.5 A25W + V45L + L149R + T215I + V258P + A276S + A364G 51.5 A25W + V45L + L149R + H219I + V258P + A276S + A364G 51.5 V45L + A117S + L149R + V258P + A276S + L281V + A364G 51.5 D9E + A25W + V45L + L149R + V258P + A276S + A364G 51.5 V45L + L149R + S214Y + V258P + A276S + A364G + S388K 51.5 A25W + V45L + L149R + T180Q + V258P + A276S + A364G 51.5 A25W + V45L + L149R + V258P + A276S + L281V + A364G 51.5 V45L + N127D + L149R + V258P + A276S + L281V + A364G 51.5 V45L + L149R + S173Y + V258P + A276S + H358T + A364G 51.5 V45L + Q61R + L149R + V258P + A276S + A364G + S388K 51.5 M28P + V45L + A117S + L149R + S214Q + V258P + A276S + 51.4 A364G + S388K V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 51.4 S388A V45N + A117S + L149R + S214Q + V258P + A276S + A364G + 51.4 S388K V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 51.4 S388K + T477K A25W + V45L + L149R + T180Q + V258P + A276S 51.4 A25W + V45L + L149R + V258P + A276S + A286S 51.4 A25W + V45L + L149R + G187S + S214E + V258P + A276S + 51.4 A364G V45L + L149R + V258P + A276S + L281V + A286E + A364G 51.4 A25W + V45L + L149R + W250Y + V258P + A276S + A364G 51.4 A25W + V45L + L149R + V258P + N260H + A276S + A364G 51.4 V45L + L149R + V258P + A276S + L281V + V350L + A364G 51.4 A25W + V45L + L149R + A170S + V258P + A276S + A364G 51.4 V45L + L149R + V258P + A276S + L281V + A286S + A364G 51.4 V45L + L149R + V258P + A276S + L281V + S282N + A364G 51.4 D11E + V45L + L149R + V258P + A276S + L281V + A364G 51.4 V45L + Q61K + L149R + V258P + A276S + L281V + A364G 51.4 V45L + L149R + T215I + V258P + A276S + L281V + A364G 51.4 A25W + V45L + S92D + L149R + V258P + A276S + A364G 51.4 V45L + L149R + S214Y + V258P + A276S + L281V + A364G 51.4 V45L + L149R + T211H + V258P + A276S + L281V + A364G 51.4 A25W + V45L + L149R + G187L + V258P + A276S + A364G 51.4 V45L + S92D + L149R + V258P + A276S + H358T + A364G 51.4 V45L + L149R + G187L + A276Q + L281V + A364G 51.4 V45L + L149R + A276Q + L281V + V350L + A364G 51.4 V45L + L149R + A276Q + L281V + A364G + S388K 51.4 V45L + A117S + L149R + S214Y + V258P + A276S + A364G + 51.4 S388K A25W + V45L + S92D + L149R + V258P + A276S 51.4 A25W + V45L + L149R + G187L + V258P + A276S 51.4 A25W + V45L + L149R + W250Y + V258P + A276S 51.4 V45L + D113T + L149R + V258P + A276S + A364G 51.3 V45L + L149R + G187K + V258P + A276S + H358T + A364G 51.3 V45L + L149R + N163H + V258P + A276S + L281V + A364G 51.3 A25W + V45L + T70R + L149R + V258P + A276S + A364G 51.3 V45L + L149R + S173Y + V258P + A276S + L281V + A364G 51.3 V45L + L149R + G187L + V258P + A276S + L281V + A364G 51.3 V45L + L149R + G187K + V258P + A276S + L281V + A364G 51.3 V45L + L149R + W250Y + V258P + A276S + H358T + A364G 51.3 V45L + L149R + T211H + V258P + A276S + A364G + S388K 51.3 V45L + L149R + N163H + V258P + A276S + A364G + S388K 51.3 V45L + T70R + L149R + A276Q + L281V + A364G 51.3 V45L + S92D + L149R + A276Q + L281V + A364G 51.3 V45L + D113T + L149R + A276Q + L281V + A364G 51.3 V45L + L149R + A276Q + L281V + Q314A + A364G 51.3 V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 51.3 S388K + S389V A25W + V45L + Q61K + L149R + V258P + A276S 51.3 D9E + A25W + V45L + L149R + V258P + A276S 51.3 V45L + T70R + L149R + V258P + A276S + A364G 51.3 V45L + L149R + V258P + A276S + A286S + A364G + S388K 51.3 A25W + V45L + L149R + S214Y + V258P + A276S + A364G 51.3 A25W + V45L + D113T + L149R + V258P + A276S + A364G 51.3 V45L + T70R + L149R + V258P + A276S + L281V + A364G 51.3 A25W + V45L + N127D + L149R + V258P + A276S + A364G 51.3 V45L + T70R + L149R + V258P + A276S + H358T + A364G 51.3 V45L + L149R + N163H + V258P + A276S + A364G 51.3 V45L + L149R + T180Q + A276Q + L281V + A364G 51.2 V45L + L149R + A276Q + L281V + A286S + A364G 51.2 A25W + V45L + L149R + A170S + V258P + A276S 51.2 A25W + V45L + T70R + L149R + V258P + A276S 51.2 A25W + V45L + L149R + S214E + V258P + A276S + A286S + 51.2 A364G V45L + L149R + V258P + A276S + A286S + H358T + A364G + 51.2 S388K V45L + L149R + H219I + V258P + A276S + L281V + A364G 51.2 A25W + V45L + A117S + L149R + V258P + A276S + A364G 51.2 A25W + V45L + L149R + N168G + V258P + A276S + A364G 51.2 V45L + L149R + N168G + A276Q + L281V + A364G 51.2 V45L + L149R + S173Y + A276Q + L281V + A364G 51.2 V45L + L149R + W250Y + A276Q + L281V + A364G 51.2 V45L + A117S + L149R + S173Y + S214Q + V258P + A276S + 51.2 A364G + S388K A25W + V45L + L149R + A276Q + A286E + A364G 51.1 A25W + V45L + L149R + A276Q + A364G + S388K 51.1 V45L + N127D + L149R + V258P + A276S + H358T + A364G 51.1 A25W + V45L + L149R + V258P + A276S 51.1 V45L + N127D + L149R + A276Q + L281V + A364G 51.1 V45L + L149R + A276Q + L281V + A286E + A364G 51.1 V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 51.1 S388K + V500T A25W + V45L + A117S + L149R + V258P + A276S 51.1 A25W + V45L + L149R + H219V + V258P + A276S + A364G 51.1 V45L + L149R + S173Y + V258P + A276S + H358T + A364G + 51.1 S388K D11E + V45L + L149R + V258P + A276S + H358T + A364G 51.1 V45L + A79C + L149R + V258P + A276S + N355G + A364G + 51.1 S388K A24K + V45L + L149R + V258P + A276S + A364G 51.1 V45L + L149R + V258P + A276S + S282N + A364G 51.1 V45L + A117S + L149R + A276Q + L281V + A364G 51.0 V45L + L149R + N260H + A276Q + L281V + A364G 51.0 V45L + A117S + L149R + T211H + S214Q + V258P + A276S + 51.0 A364G + S388K A25W + V45L + L149R + N168G + V258P + A276S 51.0 A25W + V45L + L149R + G187S + V258P + A276S 51.0 A25W + V45L + L149R + V258P + A276S + V350L 51.0 A25W + V45L + Q61R + L149R + V258P + A276S 51.0 A25W + V45L + L149R + G187L + S214E + V258P + A276S + 51.0 A364G V45L + L149R + G187S + V258P + A276S + L281V + A364G 51.0 A25W + V45L + L149R + N163H + V258P + A276S + A364G 51.0 A25W + V45L + L149R + G187K + V258P + A276S + A364G 51.0 V45N + L149R + V258P + A276S + L281V + A364G 51.0 V45L + L149R + A276Q + L281V + A364G 51.0 V45L + L149R + V258P + N260H + A276S + H358T + A364G 51.0 V45L + L149R + A276Q + S282N + A364G 51.0 V45L + S92D + A117S + L149R + S214Q + V258P + A276S + 51.0 A364G + S388K A25W + V45L + L149R + V258P + A276S + S282N 51.0 A25W + V45L + L149R + S173Y + V258P + A276S 51.0 A25W + V45L + L149R + A276Q + A286S + A364G 50.9 V45L + D113T + L149R + V258P + A276S + L281V + A364G 50.9 V45L + L149R + S214Q + V258P + A276S + L281V + A364G + 50.9 S388K V45L + D113T + L149R + V258P + A276S + H358T + A364G 50.9 A25W + V45L + L149R + T215V + V258P + A276S 50.9 V45L + L149R + N168G + V258P + A276S + H358T + A364G 50.9 V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 50.9 S388K + A472L V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 50.9 S388K + S473K A25W + V45L + L149R + T215I + V258P + A276S 50.9 A25W + V45L + L149R + T211H + V258P + A276S 50.9 A25W + V45L + L149R + V258P + A276Q 50.9 V45L + L149R + S214Q + T215V + V258P + A276S + A364G + 50.9 S388K V45L + L149R + N163H + V258P + A276S + H358T + A364G + 50.9 S388K V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 50.8 S388K + A499L V45L + L149R + V258P + A276S + V350L + A364G 50.8 V45L + A79C + A117S + L149R + V258P + A276S + A364G + 50.8 S388K A25W + V45L + D113T + L149R + A276Q + A364G 50.8 A25W + V45N + L149R + V258P + A276S + A364G 50.8 V45L + T70R + L149R + A276Q + A364G 50.8 A25W + V45L + L149R + H219I + V258P + A276S 50.8 V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 50.8 S388K + V498I M28P + V45L + L149R + V258P + A276S + A364G 50.8 A25W + V45L + T70R + L149R + A276Q + A364G 50.8 A25W + V45L + L149R + A276Q + Q314A + A364G 50.8 V45L + L149R + A170S + V258P + A276S + H358T + A364G + 50.7 S388K A25W + V45L + L149R + S214Y + V258P + A276S 50.7 V45L + L149R + S214Y + V258P + A276S + H358T + A364G 50.7 V45L + L149R + A276Q + L281V + H358T + A364G 50.7 A25W + V45L + L149R + H219V + V258P + A276S 50.7 V45L + A117S + L149R + N163H + S214Q + V258P + A276S + 50.7 A364G + S388K D11E + A25W + V45L + L149R + V258P + A276S 50.7 V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 50.7 S388K + N527H A25W + V45L + A117S + L149R + A276Q + A364G 50.7 V45L + L149R + V258P + L281V + A364G 50.7 A25W + V45L + L149R + G187L + A276Q + A364G 50.6 V45N + L149R + V258P + A276S + H358T + A364G 50.6 V45L + A117S + L149R + S214Q + V258P + A276S + N355G + 50.6 H358D + A364G + S388K + D470T + R483V V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 50.6 A364G + S388H + D470T + R483V A25W + V45L + L149R + A276Q + A364G 50.6 V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 50.6 A364G + S388K + D470T + R483V + V497E A25W + V45L + L149R + N163H + A276Q + A364G 50.6 A25W + V45L + L149R + S173Y + A276Q + A364G 50.6 A25W + V45L + L149R + A276Q + S282N + A364G 50.6 A25W + V45L + L149R + A276Q + H358T + A364G 50.6 A25W + V45L + L149R + T180Q + A276Q + A364G 50.6 V45L + A117S + L149R + V258P + A276S + H358T + A364G 50.5 V45L + L149R + A276Q + Q314A + A364G 50.5 V45L + L149R + G187K + V258P + A364G 50.5 V45L + L149R + A276Q + A286E + A364G 50.5 A25W + V45L + N127D + L149R + A276Q + A364G 50.5 A25W + V45L + L149R + A170S + A276Q + A364G 50.5 A25W + V45L + N127D + L149R + V258P + A276S 50.5 V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 50.4 S388K + T477V V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 50.4 S388K + G503L A25W + M28P + V45L + L149R + V258P + A276S + A364G 50.4 V45L + L149R + A276Q + H358T + A364G 50.4 A25W + V45L + L149R + N168G + A276Q + A364G 50.4 A25W + V45L + L149R + N260H + A276Q + A364G 50.4 V45L + A117S + L149R + G187L + S214Q + V258P + A276S + 50.4 A364G + S388K V45L + A117S + L149R + N163H + S214Q + V258P + A276S + 50.3 H358D + A364G + S388K + D470T + L530R V45L + A117S + L149R + S214Q + T215K + V258P + A276S + 50.3 A364G + S388K A25W + V45L + L149R + G187K + V258P + A276S 50.3 A25W + M28P + V45L + L149R + V258P + A276S 50.3 A25W + V45N + L149R + V258P + A276S 50.3 V45L + A117S + L149R + S214Q + V258P + A276S + N355G + 50.2 H358D + A364G + S388K + D470T V45L + N127D + L149R + A276Q + A364G 50.2 V45L + L149R + W250Y + A276Q + A364G 50.2 V45L + L149R + W250Y + V258P + A364G 50.2 V45L + L149R + N163H + A276Q + L281V + A364G 50.1 V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 50.1 Q385C + S388K A25W + V45L + L149R + S214E + T215K + V258P + A276S + 50.1 A364G M28P + V45L + L149R + V258P + A276S + L281V + A364G 50.0 V45L + L149R + A276Q + A364G + S388K 50.0 A25W + V45L + L149R + V258P + A364G 50.0 M28P + V45L + L149R + V258P + A276S + H358T + A364G 50.0 V45L + A117S + L149R + S214Q + V258P + A276S + N355G + 50.0 H358D + A364G + S388K V45L + T70R + A117S + L149R + S214Q + V258P + A276S + 50.0 L281V + H358D + A364G + S388K + G394A + D470T + R483V + C540V V45L + L149R + N168G + A276Q + A364G 50.0 V45L + A117S + L149R + A276Q + A364G 49.9 V45L + L149R + N163H + V258P + A276S + H358T + A364G 49.9 V45L + L149R + T215K + V258P + A276S + H358T + A364G 49.9 A24K + V45L + L149R + A276Q + A364G 49.9 V45L + L149R + A276Q + A286S + A364G 49.9 V45L + L149R + V258P + A364G 49.9 V45L + L149R + H219I + V258P + A276S + A364G + S388K 49.8 V45L + L149R + A170S + A276Q + A364G 49.8 V45L + L149R + T180Q + A276Q + A364G 49.8 V45L + L149R + A276Q + V350L + A364G 49.8 V45L + L149R + V258P + S282N + A364G 49.8 V45L + L149R + A276Q + A364G 49.8 V45L + L149R + A276S + A364G 49.8 V45L + L149R + T215K + V258P + A276S + A364G + S388K 49.8 V45L + A117S + L149R + S214Q + V258P + A276S + N355G + 49.8 A364G + S388K + D470T V45L + L149R + V258P + A276S 49.8 A25W + V45L + L149R + A276S + A364G 49.8 V45L + L149R + G187S + V258P + A364G 49.8 V45L + S92D + L149R + V258P + A276S + H358T + A364G + 49.7 S388K A25W + L149R + V258P + A276S + A364G 49.7 V45L + L149R + G187L + A276Q + A364G 49.7 A25W + V45L + V258P + A276S + A364G 49.6 V45L + L149R + N260H + A276Q + A364G 49.6 V45L + L149R + W250Y + V258R + A364G 49.5 V45L + L149R + N163H + A276Q + A364G 49.4 V45L + S92D + L149R + A276Q + A364G 49.4 V45L + L149R + S173Y + A276Q + A364G 49.4 V45L + S92D + L149R + V258P + A364G 49.3 V45L + L149R + W250Y + V258P + A276S + L281V + A364G 49.3 V45L + L149R + L281V + A364G 49.3 V45L + D113T + L149R + A276Q + A364G 49.2 L149R + V258P + A276S + A364G 49.2 V45L + L149R + G187S + V258R + A364G 49.1 V45L + V258P + A276S + A364G 49.1 V45L + L149R + V258R + A364G + S388K 49.1 A25W + V45L + L149R + A364G 49.0 V45L + L149R + G187K + V258R + A364G 49.0 V45L + L149R + V258P 49.0 V45L + L149R + V258R + S282N + A364G 48.9 V45L + L149R 48.8 V45L + L149R + V258R + L281V + A364G 48.7 V45L + L149R + A364G 48.7 V45L + L149R + S214Q + V258P + A276S + N355G + 48.6 A364G +S388K V45L + S92N + L149R + V258P + A364G 48.6 V45L + A117S + L149R + S214Q + V258P + A276S + 48.6 A286E +H358D + A364G + S388K A25W + V45L + L149R + S214E + V258P + A276S + 48.5 N355G +A364G V45L + L149R + G187L + V258P + A276S + A364G 48.5 V45L + L149R + V258R + A364G 48.5 V45L + L149R + V258P + A364G + S388K 48.5 A25W + V45L + L149R + A276Q + V350L + A364G 48.5 V45L + L149R + H219V + V258P + A276S + A364G + S388K 48.4 V45L + L149R + G187K + A364G 48.4 V45L + L149R + G187S + A364G 48.4 V45L + A117S + L149R + S214Q + V258P + A276S + 48.2 N355G +A364G + S388K V45L + A117S + L149R + S214Q + V258P + A276S + 48.2 H358D +A364G + Y386G + S388K + D470T + R483V V45L + L149R + W250Y 48.1 V45L + S92N + L149R + V258R + A364G 48.0 A25W + V45L + L149R + V258P + A276S + N355G + A364G 47.9 V45L + L149R + V258P + A276S + N355G + A364G + S388K 47.9 V45L + L149R + G187S 47.8 V45N + L149R 47.8 V45L + L149R + S282N 47.7 L149R + A364G 47.7 Y386G 47.7 V258P + A276Q 47.7 V258P + A276S 47.7 V45L + A117S + L149R + S214Q + V258P + A276S + 47.6 H358D +A364G + S388K + G394D + D470T + R483V A25W + L149R 47.6 V45L + A276S 47.6 V45L + S92D + L149R 47.6 A25W + A276S 47.6 Q385C 47.6 V45L + L149R + W250Y + A364G 47.5 V45L + A276Q 47.5 V45L + V258P 47.5 V45L + A117S + L149R + S214Q + V258P + A276S + 47.4 H358D +A364G + Y386G + S388K A25W + V258P 47.2 A25W + A276Q 47.1 L149R + W250Y 47.1 V45L + L149R + V258P + A276S + L281V + N355G + A364G 47.1 V45L + S388K 47.0 V45L + L149R + V258P + A276S + N355G + H358T + A364G 47.0 V45L + A364G 46.9 V45N + V258P 46.9 A276S 46.8 V258P + S388K 46.8 A25W + V45L 46.8 A276Q + S388K 46.8 A276C 46.8 A276Q 46.7 A276F 46.7 W250Y + A276Q 46.6 A79C 46.6 A276S + S388K 46.6 A276Q + L281V 46.6 V45L + L149R + V258P + A276S + N355G + A364G 46.5 A276N 46.5 W250Y + A276S 46.5 A25W + S388K 46.5 A276S + L281V 46.4 G187S + A276Q 46.3 A25W + V45L + L149R + V258P + A276S + N355G 46.3 V45L 46.3 S92D + A276S 46.3 S19T 46.2 L149R + V258R 46.2 V45N + S388K 46.2 A25W + V45L + S92D + L149R + A276Q + A364G 46.2 V45L + A117S + L149R + S214Q + V258P + A276S + 46.1 A364G +S388K + D470T + S501E H358D 46.1 A25W + A364G 46.0 V258P + L281V 46.0 L149R 46.0 V45L + L149R + H219V + V258P + A276S + H358T + A364G 46.0 A25W 46.0 V258R + A276S 46.0 V45N 45.9 G187S + A276S 45.8 G187K + A276S 45.8 I469T 45.8 V45L + S92D 45.8 V45L + L281V 45.8 V45N + W250Y 45.8 V258R + A276Q 45.8 V45L + V258R 45.8 W250Y + S388K 45.7 A25W + V45L + L149R + A276Q + N355G + A364G 45.6 V45N + G187K 45.6 A25W + V45L + L149R + S214E + V258P + A276S + 45.6 Q314A +A364G S388A 45.6 A276T 45.6 A25W + V258R 45.6 G187K + S388K 45.6 A25W + S92D 45.6 L281V + S388K 45.6 V45N + V258R 45.6 S388H 45.6 S92D 45.6 D525L 45.5 S214Q 45.5 L281V + A364G 45.5 A364G 45.5 S388L 45.5 S388R 45.5 S473G 45.5 S92D + A364G 45.5 A25W + G187S 45.4 A25W + G187K 45.4 W250Y + V258P 45.4 S92D + V258P 45.4 S389V 45.4 A20H 45.4 W495E 45.4 G187K + W250Y 45.4 Y386Y 45.4 V393H 45.4 G187L 45.4 Q61K 45.3 V45N + S92D 45.3 G187S + A364G 45.3 G187S + L281V 45.3 G187S 45.3 A286E 45.3 A276Y 45.3 V258P 45.3 Q496E 45.3 G394A 45.3 V393R 45.3 G187S + S388K 45.3 T366V 45.3 S389S 45.2 S92N 45.2 N527H 45.2 Q384A 45.2 V497D 45.2 D470T 45.2 A18V 45.2 Q496Q 45.2 Q496R 45.2 S214E 45.2 P362P 45.2 S389H 45.2 V258R 45.2 A276D 45.2 L281V 45.2 V45I 45.2 A117C 45.2 N395N 45.2 Y391Y 45.2 A24H 45.2 A472I 45.2 D470K 45.1 S473K 45.1 S473S 45.1 W495I 45.1 V497E 45.1 A24K 45.1 V45T 45.1 L471R 45.1 A472L 45.1 A20P 45.1 N395D 45.1 G394D 45.1 G394Q 45.1 G187S + V258R 45.1 S92D + G187S 45.1 V45C 45.0 N476N 45.0 G207G 45.0 A364A 45.0 D470A 45.0 N474G 45.0 D470V 45.0
Example 3: Thermostability of Xylanase Variants Using Nano-Differential Scanning Fluorimetry (DSF)
[6983] Culture supernatants grown in 96-well plate was clarified by centrifugation (5424R, Eppendorf) at 3000×g for 30 min at 4° C. Clarified supernatant thus obtained was diluted 5-times with dilution buffer in 1.5 ml Eppendorf tube (MCT-15-A, Axygen.sup.R). Dilution buffer: sodium acetate buffer (50 mM) was made by adding 4.1 g of sodium Acetate (Sigma, S2889) in 1 L of Milli-Q water and adjusting the pH to 4.0 using acetic acid. Diluted samples were subjected to centrifugation at 12,000×g for 2 min to remove any precipitates formed. Clarified supernatants were filled in nano-DSF glass capillaries (PR-0002, Nanotemper Technologies) by dipping capillary in the sample and placed in a slot if the nano-DSF instrument (Prometheus NT.48, Nanotemper Technologies). Each sample was analyzed in triplicate. Hence, total 16 samples were analyzed in 48 capillaries in a single run. In each run, purified xylanase-WT and culture supernatant-WT were used as controls. Samples were scanned from 25-65° C. at a ramp speed of 1.5° C./min. Melting temperature (T.sub.m) was obtained from first-derivative curve plotted from raw data using inbuilt software provided by Nanotemper Technologies.
[6984] Tm of the xylanase variant and the Tm of the wild-type xylanase (SEQ ID NO: 1) are presented in table 2 below. The results in table 2 shows that the xylanase variants have improved thermostability relative to the wild-type xylanase (SEQ ID NO: 1).
TABLE-US-00003 TABLE 2 Thermostability of xylanase variants of SEQ ID NO: 1 using nano-DSF Tm Variant(s) (° C.) WT 43.6 A25W + V45L + L149R + V258P + A276S + A364G 51.5 V45L + L149R + V258P + A276S + L281V + A364G 46.4 V45L + L149R + V258P + A276S + A364G + S388K 52.6 V45L + L149R + S173Y + V258P + A276S + A364G 51.9 V45L + L149R + V258P + A276S + A364G 52.1 V45L + L149R + A170S + V258P + A276S + A364G 51.6 V45L + L149R + V258P + A276Q + A364G 51.7 V45L + N127D + L149R + V258P + A276S + A364G 51.9 V45L + L149R + W250Y + V258P + A276S + A364G 51.7 V45L + L149R + T180Q + V258P + A276S + A364G 51.9 V45L + L149R + V258P + A276S + Q314A + A364G 51.9 V45L + A117S + L149R + V258P + A276S + A364G 52.0 V45L + L149R + V258P + A276S + A286E + A364G 51.5 V45L + T70R + L149R + V258P + A276S + A364G 52.2 V45L + L149R + N163H + V258P + A276S + A364G 51.2 V45L + L149R + A276Q + L281V + A364G 51.4 V45L + L149R + V258P + A276S + V350L + A364G 51.2 M28P + V45L + L149R + V258P + A276S + A364G 51.1 V45L + L149R + V258P + L281V + A364G 51.9 A25W + V45L + L149R + A276Q + A364G 51.4 V45L + L149R + A276Q + Q314A + A364G 49.2 V45L + L149R + G187K + V258P + A364G 51.7 V45L + L149R + A276Q + H358T + A364G 49.9 V45L + L149R + W250Y + A276Q + A364G 48.6 V45L + A117S + L149R + A276Q + A364G 49.4 V45L + L149R + A276Q + A286S + A364G 49.2 V45L + L149R + A170S + A276Q + A364G 49.3 V45L + L149R + T180Q + A276Q + A364G 50.0 V45L + L149R + A276Q + V350L + A364G 48.9 V45L + L149R + G187S + V258P + A364G 49.7 V45L + L149R + G187L + A276Q + A364G 49.5 V45L + L149R + N163H + A276Q + A364G 48.7 V45L + L149R + S173Y + A276Q + A364G 47.4 V45L + L149R 48.3 V45L + L149R + G187L + V258P + A276S + A364G 51.7 V45L + L149R + V258P + A364G + S388K 49.6 V45L + L149R + V258P + A276S + N355G + A364G 46.5 V45L 46.3 L149R 46.5 A79C 47.6 V45N 46.5 V45L + D11E 46.4 L149R + S388K 47.3 L149R + D11E 46.4 A364G + D11E 45.6 S388K + D11E 45.2
Example 4: Thermostability of Purified Xylanase Variants Nano-Differential Scanning Fluorimetry (DSF)
[6985] Melting temperature (T.sub.m) of purified xylanase variants was measured using nano-DSF. Purified protein was diluted to 100 ppm using 50 mM sodium acetate at pH 4.0. Sodium acetate buffer (50 mM) was prepared by adding 4.1 g of sodium acetate (Sigma, S2889) in 1 L of Milli-Q water and adjusting the pH to 4.0 using acetic acid. Diluted samples were filled in n-DSF glass capillaries (PR-0002, Nanotemper Technologies) by dipping capillary in the sample and placed in a slot of the n-DSF instrument (Prometheus NT.48, Nanotemper Technologies). Each sample was analyzed in triplicate. Hence, total 16 samples were analyzed in 48 capillaries in a single run. In each run, purified xylanase-WT was used as a control. Samples were scanned from 25-65° C. at a ramp speed of 1.5° C./min. T, was obtained from first-derivative curve plotted from raw data using inbuilt software provided by Nanotemper Technologies.
[6986] Tm of the xylanase variant and the Tm of the wild-type xylanase are presented in table 3 below. The results in table 3 shows that the xylanase variants have improved thermostability relative to the wild-type xylanase (SEQ ID NO: 1).
TABLE-US-00004 TABLE 3 Thermostability of purified xylanase variants of SEQ ID NO: 1 using nano-DSF Tm Variant(s) (° C.) WT 43.6 V45L + A79C + A117S + L149R + S214Q + V258P + A276S + 57.8 A364G + S388K + D470T + R483V V45L + A79C + A117S + L149R + S214Q + V258P + A276S + 59.1 H358D + A364G + S388K + D470T V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 57.2 A364G + S388K + D470T + R483V V45L + Q61K + A117S + L149R + S214Q + V258P + A276S + 57.9 H358D + A364G + S388K + D470T V45L + D95N + A117S + L149R + S214Q + V258P + A276S + 57.5 H358D + A364G + S388K + G394A + D470T V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 56.2 S388K + G394A + D470T + R483V V45L + A93T + A117S + L149R + S214Q + V258P + A276S + 56.5 H358D + A364G + S388K + D470T + A499Y V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 56.7 Q384A + S388K + D470T + R483V V45L + A79C + A117S + L149R + S214Q + V258P + A276S + 58.2 H358D + A364G + S388K V45L + A117S + L149R + S214Q + V258P + A276S + A364G + 55.5 S388K + D470T + R483V V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 56.9 A364G + S388K + D470T V45L + A79C + A117S + L149R + S214Q + V258P + A276S + 57.2 A364G + S388K + D470T V45L + D95N + A117S + L149R + S214Q + V258P + A276S + 56.1 H358D + A364G + S388K + S473G V45L + T70R + D95N + A117S + L149R + S214Q + V258P + 57.3 A276S + L356M + H358D + A364G + S388K V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 56.7 A364G + S388K + D470A V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 56.5 A364G + S388K + L478N V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 56.3 A364G + S388K + N395D V45L + A117S + L149R + S214Q + V258P + A276S + H358D + 56.7 A364G + S388K + T477K V45L + A117S + L149R + S214Q + V258P + A276S + L281V + 56.7 H358D + A364G + S388K D11E + V45L + A117S + L149R + S214Q + V258P + A276S + 56.5 H358D + A364G + S388K V45L + L149R + V258P + A276S + H358T + A364G 52.3 A25W + V45L + L149R + V258P + A276S + A364G 52.5 V45L + L149R + S214Q + V258P + A276S + A364G + S388K 54.5 V45L + L149R + V258P + A276S + L281V + A364G 52.5 V45L + N127D + L149R + V258P + A276S + A364G + S388K 53.4 V45L + L149R + V258P + A276S + H358T + A364G + S388K 53.7 V45L + L149R + V258P + A276S + A364G + S388K 53.3 V45L + L149R + W250Y + V258P + A276S + A364G + S388K 53.7 V45L + L149R + V258P + A276S + A286E + A364G + S388K 54.1 V45L + L149R + V258P + A276S + S282N + A364G + S388K 53.7 V45L + L149R + S214Q + V258P + A276S + H358T + A364G 53.7 A25W + V45L + L149R + V258P + A276Q + A364G 52.1 V45L + L149R + V258P + A276S + A364G 53.1 A25W + V45L + L149R + W250Y + A276Q + A364G 51.1 A25W + V45L + L149R + A276Q + L281V + A364G 51.9 A25W + V45L + L149R + A276Q + A286E + A364G 51.2 A25W + V45L + L149R + A276Q + A364G + S388K 51.5 V45L + L149R + V258P + L281V + A364G 51.3 A25W + V45L + L149R + A276Q + A364G 51.2 V45L + L149R + V258P + A364G 50.6 V45L + L149R + V258P + S282N + A364G 50.8 V45L + L149R + A276Q + A364G 49.3 V45L + L149R + A276S + A364G 51.0 V45L + L149R 48.1 V45L + L149R + A364G 48.5 V45L + L149R + V258R + A364G 50.4 V258P + A276Q 48.0 V258P + A276S 47.9 V45L + A276S 47.9 V45L + A276Q 48.1 L149R + W250Y 46.9 V258P + S388K 47.1 A276Q + S388K 47.4 W250Y + A276Q 47.5 A276S + S388K 47.5 A276Q + L281V 47.2 W250Y + A276S 46.6 A276S + L281V 47.0 G187S + A276Q 46.3 V45L + L281V 45.9 V45L 45.2 L149R 45.6 A79C 46.5 V45N 45.7 V45L + D11E 46.1 L149R + S388K 47.3 L149R + D11E 46.5 A364G + D11E 45.2 S388K + D11E 45.7
Example 5: Thermostability of Purified Xylanase Variants Under High Sulphur Dioxide
[6987] In this experiment, xylanase variants and wildtype xylanase were tested for thermostability in presence of high sulphur dioxide.
[6988] The thermostability screening assay generally includes an enzyme stress test by incubating enzymes (xylanase variants) in corn fiber extract followed by an activity test incubating the stressed enzyme in fine fiber. In the first stage, enzymes were incubated in fiber extract at application relevant conditions (pH 4.0, temperature 48-52° C.) in an Infors Multitron Pro. The plates were mixed at 600 rpm and 0.5 mL aliquots are pipetted into a 96 Fisherbrand deepwell plate and were stored at 4° C. until further use. The samples were transferred into a Fisher Scientific 24 well plate containing 2.5 mL of 3% dry solids corn fine fiber. Samples were vortexed thoroughly and placed in the Infors Multitron Pro and incubated at 48° C. for 2 hours, 600 rpm.
[6989] Upon completion of the secondary incubation, samples weere centrifuged in an Avanti J-E centrifuge at 3,500 rpm for 10 minutes at 10° C. The supernatant was gently pipetted off so as not to disturb the pelleted material. The amount of reducing sugars was determined in the supernatant via the addition of 125 uL of dinitrosalicyclic acid reagent (DNS) to 75 uL of sample. If necessary, samples are diluted using distilled water before the DNS reaction. Samples were incubated for 10 minutes at 95° C. in a C1000 Touch PCR thermocycler from BioRad. The available reducing sugars quantitatively react with the DNS causing an increase in the red-orange spectra (Miller, Analytical Chemistry 1959). The samples were centrifuged at 3,500 rpm, 30 seconds to collect condensate and cooled to ambient temperature. 150 uL of centrifuged sample was then transferred using a multichannel pipette to a Nunc F 96 well plate. Absorbance at 560 nanometers (nm) was read using a Tecan Infinite M1000.
[6990] Thermostability assay was run at pH 4.0 for two hours at 52° C., with the addition of 1000 ppm of sulfur dioxide. 500 ppm/mL of xylanase variant and wildtype xylanase enzyme were added into the fiber extract. Samples were pulled as soon as the addition of enzymes to fiber extract was completed, to be considered 100% active baseline. After two hours of incubation, all samples were added into corn fine fiber with a final concentration of 100 ppm/mL. The fine fiber was incubated for two hours, 48° C., 600 rpm. After incubation, the reducing ends were determined by absorbance at 560 nm. All treatments were run in triplicate. Absorbance values and retained activity from fiber are reported in Table 4 with ±standard deviation, n=3. The xylanase variants showed higher thermostability (increased retained activity) when compared to wildtype xylanase (SEQ ID NO: 1).
TABLE-US-00005 TABLE 4 Results of residual activities Average Average Retained Absorption, Absorption, Activity 0 hours 2 hours (% of Treatment (560 nm) (560 nm) original) WT (SEQ ID NO: 1) 0.900 (0.065) 0.138 (0.045) 15% V45L + T70R + A117S + L149R + 0.904 (0.125) 0.717 (0.056) 79% S214Q + V258P + A276S + L281V + H358D + A364G + S388K + G394A + D470T + R483V V45L + A79C + A117S + L149R + 0.912 (0.139) 0.466 (0.196) 51% S214Q + V258P + A276S + A364G + S388K + D470T + R483V V45L + A117S + L149R + S214Q + 0.889 (0.095) 0.284 (0.237) 32% V258P + A276S + H358D + A364G + S388K + D470T + R483V
Example 6
Method Description Fiber Washing Assay
[6991] The assay includes incubating wet fiber samples obtained from wet-milling plant, in the presence of enzymes, at conditions relevant to the process (pH 4, Temp ˜50° C.) and over a time period of between 1 to 4 hr. After incubation, the fiber is transferred and pressed over a screen (typically 100 micron or smaller), through which the filtrates consisting mainly of the separated starch and gluten are then collected. A number of washes are done over the screen, and the washings are collected together with the initial filtrate. The collected filtrate was then passed over a funnel filter (glass filter with 0.45 micron opening) to further separate the insoluble solids (starch and gluten) from the rest of the filtrates (mostly dissolved solids). These retained insoluble solids are washed and then oven dried to dryness. The insoluble dry mass is weighed and then analyzed for starch content
[6992] In this experiment, xylanase variants and wildtype xylanase were tested for product and performance in terms of total insoluble solid yields and starch yields. Wet-mill fiber with 8% dry solids content were treated with total of 300 pg enzyme protein per gram dry solid substrate, of which 10% (30 pg/g ds) is xylanase, and the remaining 90% consisted of the background cellulases. Cellulases are all cellulase enzymes produced by fermentation of Trichoderma reesei. The gram scale fibewashing assay was done with 2 hr incubation, at pH 4.0 and 50° C. The results are reported in Table 5 below. The xylanase variants showed superior performance when compared to wildtype xylanase (SEQ ID NO: 1).
TABLE-US-00006 TABLE 5 Results of residual activities Insolubles Yield (% w/w Starch Yield of starting (% w/w of GH5_21 Component fiber dry starting fiber (10% unless indicated) solids) dry solids) WT (SEQ ID NO: 1) 33.2% (1.8%) 26.0% (2.1%) V45L + A117S + L149R + S214Q + 35.7% (0.5%) 28.4% (1.5%) V258P + A276S + H358D + A364G + S388K + D470T + R483V V45L + A79C + A117S + L149R + 38.1% (1.5%) 30.1% (1.2%) S214Q + V258P + A276S + A364G + S388K + D470T + R483V V45L + T70R + A117S + L149R + 37.9% (0.7%) 29.9% (0.7%) S214Q + V258P + A276S + L281V + H358D + A364G + S388K + G394A + D470T + R483V
Example 7
[6993] The 10-g fiber assay uses a substrate obtained from corn fiber samples from a wet mill, which is incubated in the presence of enzymes, at conditions relevant to the process (pH 4, temperature around 50° C.) and over a time period of between 1 to 4 hrs. After incubation, the fiber was transferred and pressed over a 75-micron screen where the filtrates consisting mainly of the separated starch and gluten are then collected. A number of washes are done over the screen, and the washed materials passing through the screen are collected together with the initial filtrate. The collected filtrates are allowed to sit overnight letting the insoluble settle to the bottom of the flask. The bulk of the supernatant was aspirated via vacuum and the rest of the insolubles are then centrifuged in 50 ml conical tubes (3000 rpm for 10 min), after which the supernatant was decanted leaving a wet insoluble pellet. The wet insoluble pellet was lyophilized overnight to complete dryness. This insoluble dry mass was weighed to determine % insoluble yield (calculated on the basis of the starting fiber substrate weight), and in some cases analyzed for starch content to determine the % starch yield.
[6994] In this experiment, fiber containing 11.6% moisture were weighed into flasks to a weight of 5-gram dry solids, then added with pH 4 Na acetate buffer (˜40 mM) to a final slurry containing 8% dry solids. Wet-mill fiber with 8% dry solids content were treated with total of enzymes at a dose of 300 micrograms of protein per gram of fiber dry solids. A set (of triplicates) did not receive any enzyme treatment and was incubated only in buffer (control). All others received the experimental blend containing 270 micrograms total protein produced from a Trichoderma reesei (this protein blend comprises all naturally produced cellulase enzymes produced by fermentation of Trichoderma reese;) fermentation (The cellulase blend composition will comprise all cellulase activities expressed in T. reesei; e.g., endoglucanases, and cellobiohydrolases. Alternatively, a commercial blend is available from Sigma Aldrich, Celluclast 1.5) plus 30 micrograms of the GH5_21 xylanase (the wild type or the variants). Table 6 show the amounts of insoluble solids yields (expressed as percentages of the starting fiber weight) from treatments with the different variant and control. The results are reported in Table 6 below. The xylanase variants showed superior performance when compared to wildtype xylanase (SEQ ID NO: 1).
TABLE-US-00007 TABLE 6 RESULTS OF INSOLUBLE SOLIDS YIELDS Mean % Insoluble Difference GH5_21 Component Solids (Treatment- (10% unless indicated) Yield Control) Control (No enzyme) 29.5% 0 WT (SEQ ID NO: 1) 33.2% 3.7% V45L + T70R + A117S + L149R + 37.9% 8.5% * S214Q + V258P + A276S + L281V + H358D + A364G + S388K + G394A + D470T + R483V V45L + A117S + L149R + S214Q + 38.1% 8.7% * V258P + A276S + H358D + A364G + S388K + D470T + R483V V45L + A79C + A117S + L149R + 35.7% 6.3% * S214Q + V258P + A276S + A364G + S388K + D470T + R483V Standard error of mean = 1.3% (ANOVA, n = 3) * p-Value < 0.05 using Dunnett's method
Example 8
[6995] In this experiment, fiber containing 37.6% moisture were weighed into flasks to a weight of 5-gram dry solids, then added with pH 4 Na acetate buffer (˜40 mM) to a final slurry containing 8% dry solids. The fiber slurry were all dosed with 450 micrograms of total protein produced from a Trichoderma reesei this protein blend comprises all naturally produced cellulase enzymes produced by fermentation of Trichoderma reese;) fermentation (The cellulase blend composition will comprise all cellulase activities expressed in T. reesei; e.g., endoglucanases, and cellobiohydrolases. Alternatively, a commercial blend is available from Sigma Aldrich, Celluclast 1.5) for each gram of dry solids weight fiber. Each experimental set (of triplicates) was then added with 50 micrograms (per gram dry solid weight fiber) of the GH5_21 xylanase (wildtype or variants). One set received a higher dose of 300 micrograms of one of the GH5_21 variants to confirm a dose response. Table 7 show the amounts of starch yields (expressed as percentages of the starting fiber weight) from treatments with the different variant and control. The results are reported in Table 7 below.
TABLE-US-00008 TABLE 7 RESULTS OF STARCH YIELDS Mean % Difference GH5_21 Component Starch (Variant- (10% unless indicated) Yield WT) WT (SEQ ID NO: 1) 12.2% 0 A25W + V45L + D95N + L149R + 12.6% 0.4% A276Q + A364G + S388K A25W + V45L + L149R + V258P + 12.7% 0.5%* A276Q + A364G V45L + L149R + V258P + A276S + 12.8% 0.7%* L281V + A364G V45L + L149R + V258P + L281V + 12.5% 0.4% A364G V45L + L149R + V258P + L281V + 13.4% 1.3%* A364G (high dose) Standard error of mean = 1.3% (ANOVA, n = 3) *p-Value < 0.05 using Dunnett's method
Example 9
[6996] In this experiment, fiber containing 38.4% moisture were weighed into flasks to a weight of 10-gram dry solids, then added with pH 4 Na acetate buffer (˜40 mM) to a final slurry containing 8% dry solids. The fiber slurry were all dosed with 400 micrograms of total protein produced from a Trichoderma reesei (this protein blend comprises all naturally produced cellulase enzymes produced by fermentation of Trichoderma reesei) fermentation (The cellulase blend composition will comprise all cellulase activities expressed in T. reesei; e.g., endoglucanases, and cellobiohydrolases. Alternatively, a commercial blend is available from Sigma Aldrich, Celluclast 1.5) for each gram of dry solids weight fiber. Each experimental set (of triplicates) was then added with 25 micrograms (per gram dry solid weight fiber) of the GH5_21 xylanase, wildtype or variants. Table 8 show the amounts of insoluble solids yields (expressed as percentages of the starting fiber weight) from treatments with the different variant and control. The results are reported in Table 8 below.
TABLE-US-00009 TABLE 8 RESULTS OF INSOLUBLE SOLIDS YIELDS GH5_21 Component Mean % Insoluble Difference (10% unless indicated) Solids Yield (Variant-WT) WT (SEQ ID NO: 1) 25.6% 0 V45L + L149R 26.9% 1.3%* V45L + A79C + L149R + A364G 26.1% 0.5% V45L + L149R + A364G 26.0% 0.5%
[6997] The invention described and claimed herein is not to be limited in scope by the specific aspects herein disclosed, since these aspects are intended as illustrations of several aspects of the invention. Any equivalent aspects are intended to be within the scope of this invention. Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. In the case of conflict, the present disclosure including definitions will control.