Multisecond ligand dissociation dynamics from atomistic simulations

Steffen Wolf; Benjamin Lickert; Simon Bray; Gerhard Stock

doi:10.1038/s41467-020-16655-1

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arXiv · 2001.04212

Multisecond ligand dissociation dynamics from atomistic simulations

Steffen Wolf·Benjamin Lickert·Simon Bray·Gerhard Stock

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Abstract

Coarse-graining of fully atomistic molecular dynamics simulations is a long-standing goal in order to allow the description of processes occurring on biologically relevant timescales. For example, the prediction of pathways, rates and rate-limiting steps in protein-ligand unbinding is crucial for modern drug discovery. To achieve the enhanced sampling, we first perform dissipation-corrected targeted molecular dynamics simulations, which yield free energy and friction profiles of the molecular process under consideration. In a second step, we use these fields to perform temperature-boosted Langevin simulations which account for the desired molecular kinetics occurring on multisecond timescales and beyond. Adopting the dissociation of solvated sodium chloride as well as trypsin-benzamidine and Hsp90-inhibitor protein-ligand complexes as test problems, we are able to reproduce rates from molecular dynamics simulation and experiments within a factor of 2-20, and dissociation constants within a factor of 1-4. Analysis of the friction profiles reveals that binding and unbinding dynamics are mediated by changes of the surrounding hydration shells in all investigated systems.

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Steffen Wolf, Benjamin Lickert, Simon Bray, Gerhard Stock. 2020-01-13. Multisecond ligand dissociation dynamics from atomistic simulations. https://doi.org/10.1038/s41467-020-16655-1

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