Solvent fluctuations in hydrophobic cavity–ligand binding kinetics

Abstract

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.hydrodynamics | molecular recognition | hydrophobic interaction | Markovian processM olecular recognition and ligand binding are fundamental in various fields of molecular and biological sciences. Water is not just a passive bystander but actively participates in binding events by partially mediating the interactions between the ligand and the receptor site (1, 2). Underlying hydration effects are particularly important in the vicinity of hydrophobic protein patches or in hydrophobic confinement, where dewetting or capillary fluctuation effects significantly contribute to interactions that drive selfassembly and association (3-7).It has been indeed demonstrated that there is a direct correlation between capillary evaporation and the binding affinity of ligands to hydrophobic protein pockets (8-11). The latter can be empty, filled, or transiently hydrated depending on geometry and local polarity (12)(13)(14). Hence, it has been suggested that pockets prone to evaporation represent a general motif for molecular recognition of hydrophobic groups of ligands that are complementary to the pocket geometry and displace unfavorable water molecules (9). Such an expulsion of water from weakly hydrated cavities upon binding was indeed observed in compu...

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“…Importantly, in line with observations that wet/dry transitions can contribute to ligand binding (74,75,103), our docking results of 2GBI and its active analogs indicate that these pore blockers bind, from the intracellular side, to the hydrophobic pocket experiencing the largest water density fluctuations with the chemical scaffold of the ligand replacing the unstable hydrogen-bonded water clusters (54,84). Significant density fluctuations are also observed at a second site located on the extracellular side in the proximity of the polar/hydrophobic ring.…”

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Curvature Dependence of Hydrophobic Hydration Dynamics

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