Influence of Desolvation Barriers in Coupled Folding and Binding Kinetics of pKID-KIX

Abstract

Flexible and dynamic encounter complexes associated with coupled folding and binding can promote rapid molecular recognition of intrinsically disordered proteins (IDPs). Weak non-specific interactions between an IDP and its binding partner encourage enhanced binding rates through fly-casting, reduced orientational entropic costs, and long-lived encounter complexes associated with flexible binding partners. Here, we use coarse-grained native-centric simulations to investigate how desolvation barriers between the binding partners influence coupled folding binding kinetics of an IDP (pKID) to its target (KIX). We compare the free energy binding surface and kinetics for models with and without desolvation barriers between pKID and KIX for a range of flexibilities. We find that desolvation barriers leads to enhanced cooperativity of the coupled folding and binding over models without desolvation. Furthermore, when desolvation barriers are present, the simulated binding rate is over an order of magnitude faster when pKID is unfolded in the unbound. The sensitivity in binding rate to the flexibility of pKID can be understood, in part, by the ability of a flexible binding partner to overcome desolvation barriers locally while rigid proteins must overcome them collectively.