Engineering and Evolution of Allosteric Communication

Abstract

Allosteric regulation permits the modulation of protein activity at a site distinct from the protein active site. This regulation can be mediated by protein-protein interactions, small molecule binding, or post-translational modification - but in all cases the critical feature is that thermodynamic interactions between spatially distributed amino acids serve to couple perturbations at the allosteric site to the active site. Understanding which amino acids provide the basis for allostery is necessary to predict regulatory sites, engineer regulation, and understand how allostery might evolve. We show that analysis of amino acid sequence co-evolution can provide a practical strategy for engineering new regulation and predicting functional sites. Moreover, the observation of sparse co-evolving networks inside of proteins implies that allostery can evolve readily at a diversity of latent allosteric surfaces, and suggests a strategy for examining communication not only within, but also between proteins.