A mechanochemical protein model reveals the principles of molecular discrimination.*

Proteins need to selectively interact with specific targets among a multitude of similar molecules in the cell. Despite a firm physical understanding of pairwise binding interactions, a general theory that explains how proteins evolve high specificity is still lacking. Here, we present a genetic-mechano-chemical model of evolving protein-ligand interactions which offers a mechanistic understanding of molecular discrimination: More difficult discrimination tasks require more collective and precise interplay of structure, forces and dynamics. Proteins can achieve this through correlated mutations extending far from a binding site, which fine tune the localized interaction with the ligand. Thus, the solution of more complicated tasks requires larger proteins, and proteins become more evolvable and robust when they are even larger than the bare minimum required for discrimination. Our model makes specific predictions about the role of flexibility and shape in recognition, and how to decouple affinity and specificity. Thus, the proposed theory of molecular discrimination sheds light on a question that is often taken for granted – "why are proteins so big?" One possible answer is, "because molecular discrimination is often difficult."