Dataset Information

Interolog interfaces in protein-protein docking.

ABSTRACT: Proteins are essential elements of biological systems, and their function typically relies on their ability to successfully bind to specific partners. Recently, an emphasis of study into protein interactions has been on hot spots, or residues in the binding interface that make a significant contribution to the binding energetics. In this study, we investigate how conservation of hot spots can be used to guide docking prediction. We show that the use of evolutionary data combined with hot spot prediction highlights near-native structures across a range of benchmark examples. Our approach explores various strategies for using hot spots and evolutionary data to score protein complexes, using both absolute and chemical definitions of conservation along with refinements to these strategies that look at windowed conservation and filtering to ensure a minimum number of hot spots in each binding partner. Finally, structure-based models of orthologs were generated for comparison with sequence-based scoring. Using two data sets of 22 and 85 examples, a high rate of top 10 and top 1 predictions are observed, with up to 82% of examples returning a top 10 hit and 35% returning top 1 hit depending on the data set and strategy applied; upon inclusion of the native structure among the decoys, up to 55% of examples yielded a top 1 hit. The 20 common examples between data sets show that more carefully curated interolog data yields better predictions, particularly in achieving top 1 hits. Proteins 2015; 83:1940-1946. © 2015 The Authors. Proteins: Structure, Function, and Bioinformatics Published by Wiley Periodicals, Inc.

SUBMITTER: Alsop JD

PROVIDER: S-EPMC5054918 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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Interolog interfaces in protein-protein docking.

Alsop James D JD Mitchell Julie C JC

Proteins 20150929 11

Proteins are essential elements of biological systems, and their function typically relies on their ability to successfully bind to specific partners. Recently, an emphasis of study into protein interactions has been on hot spots, or residues in the binding interface that make a significant contribution to the binding energetics. In this study, we investigate how conservation of hot spots can be used to guide docking prediction. We show that the use of evolutionary data combined with hot spot pr ...[more]

PMID: 25740680

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Project description:BACKGROUND:Protein-protein recognition is of fundamental importance in the vast majority of biological processes. However, it has already been demonstrated that it is very hard to distinguish true complexes from false complexes in so-called cross-docking experiments, where binary protein complexes are separated and the isolated proteins are all docked against each other and scored. Does this result, at least in part, reflect a physical reality? False complexes could reflect possible nonspecific or weak associations. RESULTS:In this paper, we investigate the twilight zone of protein-protein interactions, building on an interesting outcome of cross-docking experiments: false complexes seem to favor residues from the true interaction site, suggesting that randomly chosen partners dock in a non-random fashion on protein surfaces. Here, we carry out arbitrary docking of a non-redundant data set of 198 proteins, with more than 300 randomly chosen "probe" proteins. We investigate the tendency of arbitrary partners to aggregate at localized regions of the protein surfaces, the shape and compositional bias of the generated interfaces, and the potential of this property to predict biologically relevant binding sites. We show that the non-random localization of arbitrary partners after protein-protein docking is a generic feature of protein structures. The interfaces generated in this way are not systematically planar or curved, but tend to be closer than average to the center of the proteins. These results can be used to predict biological interfaces with an AUC value up to 0.69 alone, and 0.72 when used in combination with evolutionary information. An appropriate choice of random partners and number of docking models make this method computationally practical. It is also noted that nonspecific interfaces can point to alternate interaction sites in the case of proteins with multiple interfaces. We illustrate the usefulness of arbitrary docking using PEBP (Phosphatidylethanolamine binding protein), a kinase inhibitor with multiple partners. CONCLUSIONS:An approach using arbitrary docking, and based solely on physical properties, can successfully identify biologically pertinent protein interfaces.

Dataset Information

Interolog interfaces in protein-protein docking.

Publications

Interolog interfaces in protein-protein docking.

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