Exploiting Conformational Ensembles in Modeling Protein–Protein Interactions on the Proteome Scale

Cellular functions are performed through protein–protein interactions; therefore, identification of these interactions is crucial for understanding biological processes. Recent studies suggest that knowledge-based approaches are more useful than “blind” docking for modeling at large scales. However, a caveat of knowledge-based approaches is that they treat molecules as rigid structures. The Protein Data Bank (PDB) offers a wealth of conformations. Here, we exploited an ensemble of the conformations in predictions by a knowledge-based method, PRISM. We tested “difficult” cases in a docking-benchmark data set, where the unbound and bound protein forms are structurally different. Considering alternative conformations for each protein, the percentage of successfully predicted interactions increased from ∼26 to 66%, and 57% of the interactions were successfully predicted in an “unbiased” scenario, in which data related to the bound forms were not utilized. If the appropriate conformation, or relevant template interface, is unavailable in the PDB, PRISM could not predict the interaction successfully. The pace of the growth of the PDB promises a rapid increase of ensemble conformations emphasizing the merit of such knowledge-based ensemble strategies for higher success rates in protein–protein interaction predictions on an interactome scale. We constructed the structural network of ERK interacting proteins as a case study.