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DOI	10.1073/pnas.1902719116
	Variational implicit-solvent predictions of the dry–wet transition pathways for ligand–receptor binding and unbinding kinetics
	Zhou S.; Gregor Weiß R.; Cheng L.-T.; Dzubiella J.; Andrew McCammon J.; Li B.
发表日期	2019
ISSN	0027-8424
起始页码	14989
结束页码	14994
卷号	116 期号:30
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.
英文关键词	Dry–wet transitions; Level-set method; Ligand–receptor binding/unbinding kinetics; String method; Variational implicit-solvent model
语种	英语
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
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/160361
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
推荐引用方式 GB/T 7714	Zhou S.,Gregor Weiß R.,Cheng L.-T.,等. Variational implicit-solvent predictions of the dry–wet transition pathways for ligand–receptor binding and unbinding kinetics[J],2019,116(30).
APA	Zhou S.,Gregor Weiß R.,Cheng L.-T.,Dzubiella J.,Andrew McCammon J.,&Li B..(2019).Variational implicit-solvent predictions of the dry–wet transition pathways for ligand–receptor binding and unbinding kinetics.Proceedings of the National Academy of Sciences of the United States of America,116(30).
MLA	Zhou S.,et al."Variational implicit-solvent predictions of the dry–wet transition pathways for ligand–receptor binding and unbinding kinetics".Proceedings of the National Academy of Sciences of the United States of America 116.30(2019).