globalchange  > 气候变化与战略
DOI: 10.1073/pnas.1902719116
论文题名:
Variational implicit-solvent predictions of the dry–wet transition pathways for ligand–receptor binding and unbinding kinetics
作者: Zhou S.; Gregor Weiß R.; Cheng L.-T.; Dzubiella J.; Andrew McCammon J.; Li B.
刊名: Proceedings of the National Academy of Sciences of the United States of America
ISSN: 0027-8424
出版年: 2019
卷: 116, 期:30
起始页码: 14989
结束页码: 14994
语种: 英语
英文关键词: Dry–wet transitions ; Level-set method ; Ligand–receptor binding/unbinding kinetics ; String method ; Variational implicit-solvent model
Scopus关键词: Article ; binding affinity ; binding and related phenomena ; chemical phenomena ; controlled study ; dry wet transition ; hydration ; hysteresis ; ligand binding ; Markov chain ; molecular dynamics ; phase transition ; priority journal ; reaction analysis ; receptor binding ; solvent effect ; stochastic model ; unbinding kinetics
英文摘要: 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. © 2019 National Academy of Sciences. All rights reserved.
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资源类型: 期刊论文
标识符: http://119.78.100.158/handle/2HF3EXSE/163548
Appears in Collections:气候变化与战略

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作者单位: Zhou, S., Department of Mathematics, Soochow University, Suzhou, Jiangsu 215006, China, Mathematical Center for Interdiscipline Research, Soochow University, Suzhou, Jiangsu 215006, China; Gregor Weiß, R., Laboratory of Physical Chemistry, Eidgenössische Technische Hochschule Zürich, Zürich, CH-8093, Switzerland, Institut für Physik, Humboldt-Universität zu Berlin, Berlin, D-12489, Germany; Cheng, L.-T., Department of Mathematics, University of California San Diego, San Diego, CA 92093-0112, United States; Dzubiella, J., Physikalisches Institut, Albert-Ludwigs-Universität Freiburg, Freiburg, 79104, Germany, Research Group Simulations of Energy Materials, Helmholtz-Zentrum Berlin, Berlin, 14109, Germany; Andrew McCammon, J., Department of Chemistry and Biochemistry, Department of Pharmacology, University of California San Diego, San Diego, CA 92093-0340, United States; Li, B., Department of Mathematics, University of California San Diego, San Diego, CA 92093-0112, United States

Recommended Citation:
Zhou S.,Gregor Weiß R.,Cheng L.-T.,et al. Variational implicit-solvent predictions of the dry–wet transition pathways for ligand–receptor binding and unbinding kinetics[J]. Proceedings of the National Academy of Sciences of the United States of America,2019-01-01,116(30)
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