Variational implicit-solvent predictions of the dry-wet transition pathways for ligand-receptor binding and unbinding kinetics.

Zhou S; Weiß RG; Cheng LT; Dzubiella J; McCammon JA; Li B

doi:10.1073/pnas.1902719116

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Variational implicit-solvent predictions of the dry-wet transition pathways for ligand-receptor binding and unbinding kinetics.

Zhou S Department of Mathematics, Soochow University, Suzhou 215006, Jiangsu, China.
Weiß RG Laboratory of Physical Chemistry, Eidgenössische Technische Hochschule Zürich, CH-8093 Zürich, Switzerland.
Cheng LT Department of Mathematics, University of California San Diego, La Jolla, CA 92093-0112.
Dzubiella J Physikalisches Institut, Albert-Ludwigs-Universität Freiburg, 79104 Freiburg, Germany.
McCammon JA Department of Chemistry and Biochemistry, Department of Pharmacology, University of California San Diego, La Jolla, CA 92093-0340 jmccammon@ucsd.edu bli@math.ucsd.edu.
Li B Department of Mathematics, University of California San Diego, La Jolla, CA 92093-0112; jmccammon@ucsd.edu bli@math.ucsd.edu.

2019-07-05

Published in:

Proceedings of the National Academy of Sciences of the United States of America. - 2019

ligand–receptor binding/unbinding kinetics

variational implicit-solvent model

Hydrophobic and Hydrophilic Interactions

English Ligand-receptor binding and unbinding are fundamental biomolecular processes and particularly essential to drug efficacy. Environmental water fluctuations, however, impact the corresponding thermodynamics and kinetics and thereby challenge theoretical descriptions. Here, we devise a holistic, implicit-solvent, multimethod approach to predict the (un)binding kinetics for a generic ligand-pocket model. We use the variational implicit-solvent model (VISM) to calculate the solute-solvent interfacial structures and the corresponding free energies, and combine the VISM with the string method to obtain the minimum energy paths and transition states between the various metastable ("dry" and "wet") hydration states. The resulting dry-wet transition rates are then used in a spatially dependent multistate continuous-time Markov chain Brownian dynamics simulation and the related Fokker-Planck equation calculations of the ligand stochastic motion, providing the mean first-passage times for binding and unbinding. We find the hydration transitions to significantly slow down the binding process, in semiquantitative agreement with existing explicit-water simulations, but significantly accelerate the unbinding process. Moreover, our methods allow the characterization of nonequilibrium hydration states of pocket and ligand during the ligand movement, for which we find substantial memory and hysteresis effects for binding vs. unbinding. Our study thus provides a significant step forward toward efficient, physics-based interpretation and predictions of the complex kinetics in realistic ligand-receptor systems.

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