Estimation of Protein-Ligand Unbinding Kinetics Using Non-Equilibrium Targeted Molecular Dynamics Simulations
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
Keywords
Cite
@article{arxiv.1907.10963,
title = {Estimation of Protein-Ligand Unbinding Kinetics Using Non-Equilibrium Targeted Molecular Dynamics Simulations},
author = {Steffen Wolf and Marta Amaral and Maryse Lowinski and Francois Vallée and Djordje Musil and Jörn Güldenhaupt and Matthias K. Dreyer and Jörg Bomke and Matthias Frech and Jürgen Schlitter and Klaus Gerwert},
journal= {arXiv preprint arXiv:1907.10963},
year = {2019}
}
Comments
This unedited version of the article may be downloaded for personal use only. Any other use requires prior permission of the author and the American Chemical Society. This article appeared in J. Chem. Inf. Model. (2019), 10.1021/acs.jcim.9b00592 and may be found at https://pubs.acs.org/doi/10.1021/acs.jcim.9b00592