Intermolecular Contact Potentials for Protein-Protein Interactions Extracted from Binding Free Energy Changes upon Mutation.

Abstract

Understanding and predicting the energetics of protein-protein interactions is fundamental to the structural modeling of protein complexes. Binding free energy can be approximated as a sum of pairwise atomic or residue contact energies, which are commonly inferred from contact frequencies observed in experimental protein structures. However, such statistically inferred potentials require certain assumptions and approximation. Here, we explore the possibility of deriving atomic and residue contact potentials directly from experimental binding free energy changes following mutation and present a number of such potentials. The first set of potentials is obtained by unweighted least-squares fitting and bootsrap aggregating. The second set is calculated using a weighting scheme optimized against absolute binding affinity data, so as to account for the over-representation of certain complexes, residues, and families of interactions. The congruence of the potentials with known physical chemistry is investigated. The potentials are further validated by ranking and clustering protein-protein docking poses.