(304i) Predicting Protein-Protein Interaction Interfaces, Hot Spots, and Binding Affinities

Protein interactions play an important role in various biological processes, such as cell signaling, drug delivery and disease. Predicting them requires an understanding of protein-water interactions because every protein binding process involves the protein-water interactions being disrupted, and replaced by direct interactions between the binding proteins. Characterizing protein-water interactions accurately, however, has proved to be challenging, because these interactions depend on not only the nanoscale topography, but also the precise chemical pattern presented by the protein surface. Here we propose a novel method for characterizing the strength of protein-water interactions and predicting the interface through which proteins interact with one another. Our approach relies on the application of an unfavorable biasing potential to the entire protein hydration shell. The response of the hydration shell waters to the applied potential contains a wealth of information, which we exploit. In particular, we identify the regions from which the protein hydration waters are displaced, resulting in the formation of cavities. The regions where cavities appear most readily ought to be the most hydrophobic, and we find that such thus regions are the most probable interfaces through which proteins bind to other proteins or non-polar ligands. Our method thus enables us to determine protein interaction interfaces, which we then use to determine binding free energies. Finally, our approach also enables determination of protein residues that contribute the most to the binding affinity, the so-called hot-spots.