Design Implications for an Ensemble‐based View of Proteins

Abstract

It has become clear, especially over the past decade, that conformational fluctuations in proteins can be dramatic, and that in their aggregate probability can account for a significant fraction of the total probability under native conditions. This poses potential challenges to design efforts. Namely, a designed ligand must either be compatible with one low energy conformations of the protein, or multiple higher energy conformations in order to result in a high binding affinity. Furthermore, because recent experimental results indicate that protein use the intrinsic fluctuations to facilitate their functional role, design processes that can manipulate the native state ensemble to favor or disfavor different conformations, can in principle facilitate the development of inhibitors or diagnostics. These possibilities can be explored using our ensemble‐based computational approach. I will discuss the latest results of our efforts to design peptide therapeutics based on these ideas.