title: Inferring the microscopic surface energy of protein-protein interfaces from mutation data.
abstract: 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 ΔΔG values, yielding mean energies of -48 cal mol(-1) Å(-2) for interactions between hydrophobic surfaces, -51 to -80 cal mol(-1) Å(-2) for surfaces of complementary charge, and 66-83 cal mol(-1) Å(-2) for electrostatically repelling surfaces, relative to the aqueous phase. This places the mean energy of hydrophobic surface burial at -24 cal mol(-1) Å(-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 http://life.bsc.es/pid/web/surface_energy/ and via the CCharpPPI web server http://life.bsc.es/pid/ccharppi/.
authors.affiliation: Joint BSC-IRB Research Program in Computational Biology, Life Science Department, Barcelona Supercomputing Center, Barcelona, 08034, Spain.
authors.forename: Iain H
authors.initials: IH
authors.lastname: Moal
authors.forename: Justas
authors.initials: J
authors.lastname: Dapkūnas
authors.forename: Juan
authors.initials: J
authors.lastname: Fernández-Recio
mesh_terms: D057927:Hydrophobic and Hydrophilic Interactions; D062105:Molecular Docking Simulation; D009154:Mutation / Q000502:physiology*; D011485:Protein Binding; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism*; D055672:Static Electricity; D013816:Thermodynamics
chemical_list: D011506:Proteins
keywords: binding affinity; docking; empirical modeling; hydrophobic effect; interaction energy; mutation; protein-protein interactions