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DARS (Decoys As the Reference State) potentials for protein-protein docking.

ABSTRACT: Decoys As the Reference State (DARS) is a simple and natural approach to the construction of structure-based intermolecular potentials. The idea is generating a large set of docked conformations with good shape complementarity but without accounting for atom types, and using the frequency of interactions extracted from these decoys as the reference state. In principle, the resulting potential is ideal for finding near-native conformations among structures obtained by docking, and can be combined with other energy terms to be used directly in docking calculations. We investigated the performance of various DARS versions for docking enzyme-inhibitor, antigen-antibody, and other type of complexes. For enzyme-inhibitor pairs, DARS provides both excellent discrimination and docking results, even with very small decoy sets. For antigen-antibody complexes, DARS is slightly better than a number of interaction potentials tested, but results are worse than for enzyme-inhibitor complexes. With a few exceptions, the DARS docking results are also good for the other complexes, despite poor discrimination, and we show that the latter is not a correct test for docking accuracy. The analysis of interactions in antigen-antibody pairs reveals that, in constructing pairwise potentials for such complexes, one should account for the asymmetry of hydrophobic patches on the two sides of the interface. Similar asymmetry does occur in the few other complexes with poor DARS docking results.

SUBMITTER: Chuang GY

PROVIDER: S-EPMC2567923 | biostudies-literature | 2008 Nov

REPOSITORIES: biostudies-literature

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DARS (Decoys As the Reference State) potentials for protein-protein docking.

Chuang Gwo-Yu GY Kozakov Dima D Brenke Ryan R Comeau Stephen R SR Vajda Sandor S

Biophysical journal 20080801 9

Decoys As the Reference State (DARS) is a simple and natural approach to the construction of structure-based intermolecular potentials. The idea is generating a large set of docked conformations with good shape complementarity but without accounting for atom types, and using the frequency of interactions extracted from these decoys as the reference state. In principle, the resulting potential is ideal for finding near-native conformations among structures obtained by docking, and can be combined ...[more]

PMID: 18676649

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Project description:BACKGROUND: Accurate description of protein interaction with aqueous solvent is crucial for modeling of protein folding, protein-protein interaction, and drug design. Efforts to build a working description of solvation, both by continuous models and by molecular dynamics, yield controversial results. Specifically constructed knowledge-based potentials appear to be promising for accounting for the solvation at the molecular level, yet have not been used for this purpose. RESULTS: We developed original knowledge-based potentials to study protein hydration at the level of atom contacts. The potentials were obtained using a new Monte Carlo reference state (MCRS), which simulates the expected probability density of atom-atom contacts via exhaustive sampling of structure space with random probes. Using the MCRS allowed us to calculate the expected atom contact densities with high resolution over a broad distance range including very short distances. Knowledge-based potentials for hydration of protein atoms of different types were obtained based on frequencies of their contacts at different distances with protein-bound water molecules, in a non-redundant training data base of 1776 proteins with known 3D structures. Protein hydration sites were predicted in a test set of 12 proteins with experimentally determined water locations. The MCRS greatly improves prediction of water locations over existing methods. In addition, the contribution of the energy of macromolecular solvation into total folding free energy was estimated, and tested in fold recognition experiments. The correct folds were preferred over all the misfolded decoys for the majority of proteins from the improved Rosetta decoy set based on the structure hydration energy alone. CONCLUSION: MCRS atomic hydration potentials provide a detailed distance-dependent description of hydropathies of individual protein atoms. This allows placement of water molecules on the surface of proteins and in protein interfaces with much higher precision. The potentials provide a means to estimate the total solvation energy for a protein structure, in many cases achieving a successful fold recognition. Possible applications of atomic hydration potentials to structure verification, protein folding and stability, and protein-protein interactions are discussed.

Project description:BACKGROUND: For over 30 years potentials of mean force have been used to evaluate the relative energy of protein structures. The most commonly used potentials define the energy of residue-residue interactions and are derived from the empirical analysis of the known protein structures. However, single-body residue 'environment' potentials, although widely used in protein structure analysis, have not been rigorously compared to these classical two-body residue-residue interaction potentials. Here we do not try to combine the two different types of residue interaction potential, but rather to assess their independent contribution to scoring protein structures. RESULTS: A data set of nearly three thousand monomers was used to compare pairwise residue-residue 'contact-type' propensities to single-body residue 'contact-count' propensities. Using a large and standard set of protein decoys we performed an in-depth comparison of these two types of residue interaction propensities. The scores derived from the contact-type and contact-count propensities were assessed using two different performance metrics and were compared using 90 different definitions of residue-residue contact. Our findings show that both types of score perform equally well on the task of discriminating between near-native protein decoys. However, in a statistical sense, the contact-count based scores were found to carry more information than the contact-type based scores. CONCLUSION: Our analysis has shown that the performance of either type of score is very similar on a range of different decoys. This similarity suggests a common underlying biophysical principle for both types of residue interaction propensity. However, several features of the contact-count based propensity suggests that it should be used in preference to the contact-type based propensity. Specifically, it has been shown that contact-counts can be predicted from sequence information alone. In addition, the use of a single-body term allows for efficient alignment strategies using dynamic programming, which is useful for fold recognition, for example. These facts, combined with the relative simplicity of the contact-count propensity, suggests that contact-counts should be studied in more detail in the future.

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DARS (Decoys As the Reference State) potentials for protein-protein docking.

Publications

DARS (Decoys As the Reference State) potentials for protein-protein docking.

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