The present invention relates to an improved method for drug discovery. In particular the present invention provides a method of identifying compounds capable of binding to a functional conformational state of a protein of interest or protein fragment thereof, said method comprising the steps of: (a) Binding a function-modifying antibody to the target protein of interest or a fragment thereof to provide an antibody-constrained protein or fragment, wherein the antibody has binding kinetics with the protein or fragment which are such that it has a low dissociation rate constant, (b) Providing a test compound which has a low molecular weight, (c) Evaluating whether the test compound of step b) binds the antibody constrained protein or fragment, and (d) Select a compound from step c) based on the ability to bind to the protein or fragment thereof.

A method for modification and/or evaluation of ligand-protein and protein-protein systems is provided. Specifically, the method involves generating a final set of ligand or protein poses based on an initial set of ligand or protein poses. The method considers a variety of tools that can be applied to each pose. Energy scoring of each pose is performed based on results obtained from application of one or more of these tools. The design of the method allows for flexibility in which tools are used, the order in which they are used, and input parameters used for the different tools. This flexibility allows a user of the method to select a level of precision desired for a particular ligand-protein and protein-protein system that is being modified and/or evaluated.

A method is disclosed for enhancing the simulation of the interaction between at least a first and a second molecular system, the interaction resulting from actual attraction and repulsion forces between the at least a first and a second molecular system. The method comprises applying an additional virtual electrostatic force between the at least a first and a second molecular system, which force has a functional form of the type of a modulated electrostatic interaction.

The invention relates to amino acid sequence variants of a lipase with improved activity for catalyzing synthesis reactions and methods of preparing the variants. The methods include predicting amino acid sites for change based on computational models of the protein structure in non-aqueous conditions, and expressing the protein in a prokaryotic host for subsequent purification and use. The enzyme sequence variants described have a three to nine-fold improvement in synthesis activity over the parent protein sequence.

Polynucleotide sequencing generates multiple reads of a polynucleotide molecule. Many or all of the reads may contain errors. Trace reconstruction takes multiple reads generated by a polynucleotide sequencer and uses those multiple reads to reconstruct accurately the nucleotide sequence. The types of errors are substitutions, deletions, and insertions. The location of an error in a read is identified by comparing the sequence of the read to the other reads. The type of error is determined by comparing both the base call of the read at the error location and base calls of the read and other reads in a look-ahead window that includes base calls adjacent to the error location. A consensus output sequence is developed from the sequences of the multiple reads and identification of the error types for errors in the reads.

The disclosure provides a FRET-based protein interaction assay that is capable of determining the dissociation constant for interactions between two proteins even if protein contaminants are present.

The present invention relates to inhibitors of protein-protein interactions (PPI). Specifically, the present invention relates to a structural informatics approach to designing peptidomimetic macrocycles containing an amino acid warhead for ligand-directed covalent modification of cysteine and lysine-containing proteins for the treatment of diseases such as cancer. Further included is the targeting of components of the BCL2 signaling pathway, specifically BCL2-A1 and MCL-1.

Methods and systems are described to provide computerized trajectory-based methods to represent translocon-associated protein trajectories, provide proteins or protein sequences with desired translocon-associated biogenesis features, screening proteins or protein sequences to provide proteins or protein sequences with desired translocon-associated biogenesis features, screening translocon-associated biogenesis feature determinants to provide proteins or protein sequences with desired translocon-associated biogenesis features, identifying translocon-associated biogenesis feature determinants of a given protein sequence, computer-based protein sequence identification methods, computer-based methods for identifying correlations in a set of protein sequences, computer-based methods for identifying correlations between experimental data and computer-generated data in a protein sequence, and computer-based methods for determining which modifications of a protein sequence do not substantially affect a translocon-associated biogenesis feature of the protein sequence.

Systems and methods are provided for predicting cardiotoxicity of molecular parameters of a compound. A computer can provide as input to a machine learning algorithm the molecular parameters of the compound. The molecular parameters can include at least structural information about the compound. The machine learning algorithm can have been trained using respective molecular parameters of compounds known to have cardiotoxicity and of compounds known not to have cardiotoxicity. The computer can receive as output from the machine learning algorithm a representation of the predicted cardiotoxicity of each molecular parameter of at least a subset of the molecular parameters of the compound.

The invention describes an explicit solvent all-atom molecular dynamics methodology (SILCS: Site Identification by Ligand Competitive Saturation) that uses small aliphatic and aromatic molecules plus water molecules to map the affinity pattern of a large molecule for hydrophobic groups, aromatic groups, hydrogen bond donors, and hydrogen bond acceptors. By simultaneously incorporating ligands representative of all these functionalities, the method is an in silico free energy-based competition assay that generates three-dimensional probability maps of fragment binding (FragMaps) indicating favorable fragment:large molecule interactions. The FragMaps may be used to qualitatively inform the design of small-molecule ligands or as scoring grids for high-throughput in silico docking that incorporates both an atomic-level description of solvation and the large molecule's flexibility.