Kinetics and Free Energy of Ligand Dissociation Using Weighted Ensemble Milestoning

TL;DR

This paper demonstrates that weighted ensemble milestoning (WEM) effectively simulates ligand-receptor dissociation dynamics, accurately reproducing timescales and free energy profiles, and introduces an improved WEM-RR scheme for enhanced accuracy in binding studies.

Contribution

The authors develop and validate a modified WEM scheme called WEM-RR that improves accuracy in ligand-receptor kinetics and thermodynamics without additional computational cost.

Findings

WEM reproduces ion pair dissociation timescale and free energy profiles.

WEM-RR yields ligand residence times and free energies consistent with experiments.

WEM efficiently computes binding/unbinding observables and estimates rate constants.

Abstract

We consider the recently developed weighted ensemble milestoning (WEM) scheme [J. Chem. Phys. 152, 234114 (2020)], and test its capability of simulating ligand-receptor dissociation dynamics. We performed WEM simulations on the following host-guest systems: Na$^+$/Cl$^-$ ion pair and 4-hydroxy-2-butanone (BUT) ligand with FK506 binding protein (FKBP). As proof or principle, we show that the WEM formalism reproduces the Na$^+$/Cl$^-$ ion pair dissociation timescale and the free energy profile obtained from long conventional MD simulation. To increase accuracy of WEM calculations applied to kinetics and thermodynamics in protein-ligand binding, we introduced a modified WEM scheme called weighted ensemble milestoning with restraint release (WEM-RR), which can increase the number of starting points per milestone without adding additional computational cost. WEM-RR calculations obtained a ligand residence time and binding free energy in agreement with experimental and previous computational results. Moreover, using the milestoning framework, the binding time and rate constants, dissociation constant and the committor probabilities could also be calculated at a low computational cost. We also present an analytical approach for estimating the association rate constant ($k_{\text{on}}$) when binding is primarily diffusion driven. We show that the WEM method can efficiently calculate multiple experimental observables describing ligand-receptor binding/unbinding and is a promising candidate for computer-aided inhibitor design.