Ligand unbinding mechanisms and kinetics for T4 lysozyme mutants from tauRAMD simulations

TL;DR

This study uses tauRAMD simulations to predict ligand unbinding kinetics for T4 lysozyme mutants, revealing key egress routes and metastable states that influence drug residence time and efficacy.

Contribution

The paper demonstrates that tauRAMD can accurately predict ligand dissociation rates and elucidate unbinding pathways, advancing computational drug kinetics prediction methods.

Findings

tauRAMD predicts relative dissociation rates consistent with experiments

Ligand egress via the main route determines tau values

Metastable states along pathways slow down dissociation

Abstract

The protein-ligand residence time, tau, influences molecular function in biological networks and has been recognized as an important determinant of drug efficacy. To predict tau, computational methods must overcome the problem that tau often exceeds the timescales accessible to conventional molecular dynamics (MD) simulation. Here, we apply the tau-Random Acceleration Molecular Dynamics (tauRAMD) method to a set of kinetically characterized complexes of T4 lysozyme mutants with engineered binding cavities. tauRAMD yields relative ligand dissociation rates in good accordance with experiments and thereby allows a comprehensive characterization of the ligand egress routes and determinants of tau. Although ligand dissociation by multiple egress routes is observed, we find that egress via the predominant route determines the value of tau. We also find that the presence of metastable states along egress pathways slows down protein-ligand dissociation. These physical insights could be exploited in the rational optimization of the kinetic properties of drug candidates.