Estimation of Protein-Ligand Unbinding Kinetics Using Non-Equilibrium Targeted Molecular Dynamics Simulations

TL;DR

This study demonstrates that non-equilibrium targeted molecular dynamics simulations can effectively estimate protein-ligand unbinding kinetics, correlating well with experimental data and revealing molecular factors influencing unbinding rates.

Contribution

The paper introduces a novel application of non-equilibrium targeted molecular dynamics to predict unbinding rates and elucidate molecular determinants affecting ligand residence times.

Findings

Mean non-equilibrium work correlates with unbinding rates.

Electrostatic and van der Waals interactions influence unbinding.

Transient electrostatic interactions can facilitate unbinding in rigid ligands.

Abstract

We here report on non-equilibrium targeted Molecular Dynamics simulations as tool for the estimation of protein-ligand unbinding kinetics. Correlating simulations with experimental data from SPR kinetics measurements and X-ray crystallography on two small molecule compound libraries bound to the N-terminal domain of the chaperone Hsp90, we show that the mean non-equilibrium work computed in an ensemble of trajectories of enforced ligand unbinding is a promising predictor for ligand unbinding rates. We furthermore investigate the molecular basis determining unbinding rates within the compound libraries. We propose ligand conformational changes and protein-ligand nonbonded interactions to impact on unbinding rates. Ligands may remain longer at the protein if they exhibit strong electrostatic and/or van der Waals interactions with the target. In the case of ligands with rigid chemical scaffold that exhibit longer residence times however, transient electrostatic interactions with the protein appear to facilitate unbinding. Our results imply that understanding the unbinding pathway and the protein-ligand interactions along this path is crucial for the prediction of small molecule ligands with defined unbinding