The Subtle Trade-Off between Evolutionary and Energetic Constraints in Protein–Protein Interactions

Life machinery, although overwhelmingly complex, is rooted on a rather limited number of molecular processes. One of the most important is protein–protein interaction. Metabolic regulation, protein folding control, and cellular motility are examples of processes based on the fine-tuned interaction of several protein partners. The region on the protein surface devoted to the recognition of a specific partner is essential for the function of the protein and is, therefore, likely to be conserved during evolution. On the other hand, the physical chemistry of amino acids underlies the mechanism of interactions. Both evolutionary and energetic constraints can then be used to build scoring functions capable of recognizing interaction sites. Our working hypothesis is that residues within the interaction interface tend at the same time to be evolutionarily conserved (to preserve their function) and to provide little contribution to the internal stabilization of the structure of their cognate protein, to facilitate...