Inferring the microscopic surface energy of protein-protein interfaces from mutation data

Mutations at protein-protein recognition sites alter binding strength by altering the chemical nature of the interacting surfaces. We present a simple surface energy model, parameterized with empirical G values, yielding mean energies of -48 calmol(-1)angstrom(-2) for interactions between hydrophobic surfaces, -51 to -80 calmol(-1)angstrom(-2) for surfaces of complementary charge, and 66-83 calmol(-1)angstrom(-2) for electrostatically repelling surfaces, relative to the aqueous phase. This places the mean energy of hydrophobic surface burial at -24 calmol(-1)angstrom(-2). Despite neglecting configurational entropy and intramolecular changes, the model correlates with empirical binding free energies of a functionally diverse set of rigid-body interactions (r=0.66). When used to rerank docking poses, it can place near-native solutions in the top 10 for 37% of the complexes evaluated, and 82% in the top 100. The method shows that hydrophobic burial is the driving force for protein association, accounting for 50-95% of the cohesive energy. The model is available open-source from and via the CCharpPPI web server . Proteins 2015; 83:640-650. (c) 2015 Wiley Periodicals, Inc.