期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 110, 期 4, 页码 1197-1202出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1221231110
关键词
hydrodynamics; molecular recognition; hydrophobic interaction; Markovian process
资金
- Deutsche Forschungsgemeinschaft (DFG) Grant [Za153/19-2]
- Department of Medicinal Chemistry, The University of Utah
- Extreme Science and Engineering Discovery Environment (XSEDE) supercomputers [TG-CHE120086]
- National Science Foundation (NSF) Grant [OCI-1053575]
- NSF
- National Institutes of Health
- Howard Hughes Medical Institute
- National Biomedical Computation Resource
- Center for Theoretical Biological Physics
- DFG
- Direct For Mathematical & Physical Scien
- Division Of Physics [1308264] Funding Source: National Science Foundation
- Div Of Molecular and Cellular Bioscience
- Direct For Biological Sciences [1020765] Funding Source: National Science Foundation
- Office of Advanced Cyberinfrastructure (OAC)
- Direct For Computer & Info Scie & Enginr [0910735] Funding Source: National Science Foundation
Water plays a crucial part in virtually all protein-ligand binding processes in and out of equilibrium. Here, we investigate the role of water in the binding kinetics of a ligand to a prototypical hydrophobic pocket by explicit-water molecular dynamics (MD) simulations and implicit diffusional approaches. The concave pocket in the unbound state exhibits wet/dry hydration oscillations whose magnitude and time scale are significantly amplified by the approaching ligand. In turn, the ligand's stochastic motion intimately couples to the slow hydration fluctuations, leading to a sixfold-enhanced friction in the vicinity of the pocket entrance. The increased friction considerably decelerates association in the otherwise barrierless system, indicating the importance of molecular-scale hydrodynamic effects in cavity-ligand binding arising due to capillary fluctuations. We derive and analyze the diffusivity profile and show that the mean first passage time distribution from the MD simulation can be accurately reproduced by a standard Brownian dynamics simulation if the appropriate position-dependent friction profile is included. However, long-time decays in the water-ligand (random) force autocorrelation demonstrate violation of the Markovian assumption, challenging standard diffusive approaches for rate prediction. Remarkably, the static friction profile derived from the force correlations strongly resembles the profile derived on the Markovian assumption apart from a simple shift in space, which can be rationalized by a time-space retardation in the ligand's downhill dynamics toward the pocket. The observed spatiotemporal hydrodynamic coupling may be of biological importance providing the time needed for conformational receptor-ligand adjustments, typical of the induced-fit paradigm.
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