Multisecond ligand dissociation dynamics from atomistic simulations

Steffen Wolf (), Benjamin Lickert, Simon Bray and Gerhard Stock ()
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Steffen Wolf: Institute of Physics, Albert Ludwigs University
Benjamin Lickert: Institute of Physics, Albert Ludwigs University
Simon Bray: Institute of Physics, Albert Ludwigs University
Gerhard Stock: Institute of Physics, Albert Ludwigs University

Nature Communications, 2020, vol. 11, issue 1, 1-8

Abstract: 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 perform dissipation-corrected targeted molecular dynamics simulations, which yield free energy and friction profiles of molecular processes under consideration. Subsequently, we use these fields to perform temperature-boosted Langevin simulations which account for the desired kinetics occurring on multisecond timescales and beyond. Adopting the dissociation of solvated sodium chloride, trypsin-benzamidine and Hsp90-inhibitor protein-ligand complexes as test problems, we 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 friction profiles reveals that binding and unbinding dynamics are mediated by changes of the surrounding hydration shells in all investigated systems.

Date: 2020
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DOI: 10.1038/s41467-020-16655-1

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