A simple physical model for binding energy hot spots in protein–protein complexes

Protein–protein recognition plays a central role in most biological processes. Although the structures of many protein–protein complexes have been solved in molecular detail, general rules describing affinity and selectivity of protein–protein interactions do not accurately account for the extremely diverse nature of the interfaces. We investigate the extent to which a simple physical model can account for the wide range of experimentally measured free energy changes brought about by alanine mutation at protein–protein interfaces. The model successfully predicts the results of alanine scanning experiments on globular proteins (743 mutations) and 19 protein–protein interfaces (233 mutations) with average unsigned errors of 0.81 kcal/mol and 1.06 kcal/mol, respectively. The results test our understanding of the dominant contributions to the free energy of protein–protein interactions, can guide experiments aimed at the design of protein interaction inhibitors, and provide a stepping-stone to important applications such as interface redesign.