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

Shenggao Zhou Soochow University R. G. Weiss ETH Zurich Li-Tien Cheng University of California, San Diego Joachim Dzubiella University of Freiburg J. Andrew McCammon University of California, San Diego Bo Li University of California, San Diego

Numerical Analysis and Scientific Computing Data Analysis, Bio-Statistics, Bio-Mathematics mathscidoc:2005.25001

Proceedings of the National Academy of Sciences of the United States of America, 116, (30), 14989–14994, 2019.7
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.
Level-set method; Multi-state Brownian dynamics; Generalized Fokker-Planck; Variational implicit-solvent model
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@inproceedings{shenggao2019variational,
  title={Variational implicit-solvent predictions of the dry-wet transition pathways for ligand-receptor binding and unbinding kinetics},
  author={Shenggao Zhou, R. G. Weiss, Li-Tien Cheng, Joachim Dzubiella, J. Andrew McCammon, and Bo Li},
  url={http://archive.ymsc.tsinghua.edu.cn/pacm_paperurl/20200522172854734057690},
  booktitle={Proceedings of the National Academy of Sciences of the United States of America},
  volume={116},
  number={30},
  pages={14989–14994},
  year={2019},
}
Shenggao Zhou, R. G. Weiss, Li-Tien Cheng, Joachim Dzubiella, J. Andrew McCammon, and Bo Li. Variational implicit-solvent predictions of the dry-wet transition pathways for ligand-receptor binding and unbinding kinetics. 2019. Vol. 116. In Proceedings of the National Academy of Sciences of the United States of America. pp.14989–14994. http://archive.ymsc.tsinghua.edu.cn/pacm_paperurl/20200522172854734057690.
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