Zhou S Weiß RG Cheng LT Dzubiella J McCammon JA Li B 2019 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. application/pdf https://sonar.ch/global/documents/175602 eng info:eu-repo/semantics/altIdentifier/doi/10.1073/pnas.1902719116 info:eu-repo/semantics/altIdentifier/pmid/31270236 info:eu-repo/semantics/openAccess Proceedings of the National Academy of Sciences of the United States of America. - 2019 dry–wet transitions level-set method ligand–receptor binding/unbinding kinetics string method variational implicit-solvent model Hydrophobic and Hydrophilic Interactions Kinetics Ligands Molecular Docking Simulation Molecular Dynamics Simulation Protein Binding Protein Conformation Solvents Variational implicit-solvent predictions of the dry-wet transition pathways for ligand-receptor binding and unbinding kinetics. http://purl.org/coar/resource_type/c_6501