Effects of electrostatic interactions on ligand dissociation kinetics

TL;DR

This study uses molecular dynamics simulations to analyze how electrostatic interactions influence ligand unbinding kinetics, highlighting the importance of explicit-ion modeling over implicit approaches for accurate predictions.

Contribution

The paper demonstrates that explicit-ion electrostatic modeling provides more accurate unbinding rates than implicit methods and explores various facilitated dissociation regimes.

Findings

Explicit-ion simulations predict lower unbinding rates than implicit models.

Facilitated dissociation regimes depend on ligand and ion concentrations.

Intermediate ligand concentrations show non-electrostatic binding effects.

Abstract

We study unbinding of multivalent cationic ligands from oppositely charged polymeric binding sites sparsely grafted on a flat neutral substrate. Our molecular dynamics (MD) simulations are suggested by single-molecule studies of protein-DNA interactions. We consider univalent salt concentrations spanning roughly a thousandfold range, together with various concentrations of excess ligands in solution. To reveal the ionic effects on unbinding kinetics of spontaneous and facilitated dissociation mechanisms, we treat electrostatic interactions both at a Debye-H\"{u}ckel (DH, or `implicit' ions, i.e., use of an electrostatic potential with a prescribed decay length) level, as well as by the more precise approach of considering all ionic species explicitly in the simulations. We find that the DH approach systematically overestimates unbinding rates, relative to the calculations where all ion pairs are present explicitly in solution, although many aspects of the two types of calculation are qualitatively similar. For facilitated dissociation (FD, acceleration of unbinding by free ligands in solution) explicit ion simulations lead to unbinding at lower free ligand concentrations. Our simulations predict a variety of FD regimes as a function of free ligand and ion concentrations; a particularly interesting regime is at intermediate concentrations of ligands where non-electrostatic binding strength controls FD. We conclude that explicit-ion electrostatic modeling is an essential component to quantitatively tackle problems in molecular ligand dissociation, including nucleic-acid-binding proteins.