期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 116, 期 30, 页码 14989-14994出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1902719116
关键词
ligand-receptor binding/unbinding kinetics; dry-wet transitions; variational implicit-solvent model; level-set method; string method
资金
- NSF of Jiangsu Province, China [BK20160302]
- NSFC (National Natural Science Foundation of China) [NSFC 21773165, NSFC 11601361]
- Soochow University [Q410700415]
- Deutsche Forschungsgemeinschaft
- European Research Council within the Consolidator Grant [646659-NANOREACTOR]
- NIH, National Biomedical Computation Resource
- San Diego Supercomputer Center
- NSF [DMS-1620487]
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 FokkerPlanck 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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