Allostery and Conformational Dynamics in Protein Evolution

Abstract

The critical role of protein dynamics has become well recognized in various biological functions, including allosteric signaling and protein ligand recognition electron transfer. Likewise, in protein evolution, the classical view of the one sequence-one structure-one function paradigm is now being extended to a new view: an ensemble of conformations in equilibrium that can evolve new functions. Therefore, understanding inherent structural dynamics are crucial to obtain a more complete picture of protein evolution. A small local structural change due to a single mutation can lead to a large difference in conformational dynamics, even at quite distant residues due to allostery. We have recently analyzed evolution of different protein families including GFP proteins, beta-lactamase inhibitors, and nuclear receptors and observed that alteration of conformational dynamics through allosteric regulations leads to functional changes. Moreover, our site-specific dynamics-based metric reveals that enzymatic function is regulated by dynamically-coupled residues, which forms an allosteric communication network with the active sites. Disease causing mutations trigger a global loss in dynamic coupling, which disrupts the communication network ultimately inhibiting function. Analysis of over 200 missense mutations also shows that Gaucher disease (GD) mutations are abundant at dynamic allosteric residue coupling sites which we call DARC spots. Further tests using 75 human enzymes revealed that diseases emerging from DARC spot mutations are not isolated to GD; indeed, this phenomenon is observed across the proteome.