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Publication Abstract from PubMed

We here report on nonequilibrium targeted molecular dynamics simulations as a 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 nonequilibrium 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 a rigid chemical scaffold that exhibit longer residence times, 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 kinetics.

Estimation of Protein-Ligand Unbinding Kinetics Using Non-Equilibrium Targeted Molecular Dynamics Simulations.,Wolf S, Amaral M, Lowinski M, Vallee F, Musil D, Guldenhaupt J, Dreyer MK, Bomke J, Frech M, Schlitter J, Gerwert K J Chem Inf Model. 2019 Dec 23;59(12):5135-5147. doi: 10.1021/acs.jcim.9b00592., Epub 2019 Nov 22. PMID:31697501^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.