Mechanistic Roles of Electrostatic Interactions in the Molecular Recognition of Intrinsically Disordered Proteins

Abstract

Electrostatic interactions could play important roles in the molecular recognition process of intrinsically disordered proteins (IDPs) as many IDPs and the recognition elements contain charged residues. Previous studies have demonstrated that electrostatic forces could accelerate the encounter process via electrostatic steering effect and increase the efficiency of binding upon encounter for several IDPs. To further investigate the universal role of electrostatic interactions in IDPs molecular recognition, we collected the experimentally determined binding kinetics of IDPs. For many studied IDPs, the association rate constants are reduced for about ten folds when the salt concentration increases from low (~50 mM) to high (~500 mM), indicating the presence of favorable electrostatic interactions. We further performed molecular dynamics simulations using structure‐based coarse‐grained models. Simulations predicted that long‐range electrostatic interactions accelerate the binding rate in a range consistent with experimental results. Simulations also revealed that electrostatic forces generally enhance the binding kinetics by increasing the encounter rate and by enhancing the evolving efficiency. Correlating the charge density with binding kinetics revealed that the overall charge density is relate with enhancement of the capture rate constant and the charge distribution affects both the evolution rate constant and escape rate constant. Analysis of the transition path times showed that electrostatic interactions stabilize the intermediate state along the binding process. Besides affecting the binding kinetics, electrostatic interactions also redistributed the flux among multiple parallel binding transition paths. As a summary, our results suggest that favorable electrostatic interactions are present in many IDPs recognition processes. Under physiological salt concentrations, electrostatic interactions are expected to enhance the binding rate constant by several folds.Support or Funding InformationThis work was supported by Hubei University of Technology