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

DOI10.1073/PNAS.1902719116MaRDI QIDQ5218549zbMATH OpenOpenAlexWikidataFDO

Authors Shenggao Zhou, R. Gregor Weiß, Li-Tien Cheng, Joachim Dzubiella, J. Andrew McCammon, Bo Li

Publication date 4 March 2020

Published in Proceedings of the National Academy of Sciences (Search for Journal in Brave)

Full work available at URL https://arxiv.org/abs/1906.07269

Mathematics Subject Classification ID

Physiological flows (76Z05) Biochemistry, molecular biology (92C40)

Abstract: 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, multi-method 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 multi-state continuous-time Markov chain Brownian dynamics simulations, 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 semi-quantitative agreement with existing explicit-water simulations, but significantly accelerate the unbinding process. Moreover, our methods allow the characterization of non-equilibrium hydration states of pocket and ligand during the ligand movement, for which we find substantial memory and hysteresis effects for binding versus unbinding. Our study thus provides a significant step forward towards efficient, physics-based interpretation and predictions of the complex kinetics in realistic ligand-receptor systems.

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(7)

• The calculus of boundary variations and the dielectric boundary force in the Poisson-Boltzmann theory for molecular solvation
• Theory of kinetics of multistep ligand-receptor assembly in dissipating and fluctuating environments
• A generalized Rayleigh-Plesset equation for ions with solvent fluctuations
• Minimizers for the Cahn-Hilliard energy functional under strong anchoring conditions
• A method to calculate binding equilibrium concentrations in the allosteric ternary complex model that supports ligand depletion
• Fast iterative method for local steric Poisson-Boltzmann theories in biomolecular solvation
• Neural network Poisson-Boltzmann electrostatics for biomolecular interactions

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