Interplay between Hydrodynamics and the Free Energy Surface in the Assembly of Nanoscale Hydrophobes

Morrone, Joseph A.; Li, Jinyuan; Berne, B. J.

doi:10.1021/jp209568n

Cited by 55 publications

(90 citation statements)

References 71 publications

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“…The characteristics of the friction profile are qualitatively similar to those calculated between associating fullerenes and hydrophobic plates (35,36). By construction, the diffusivity profile DðzÞ derived from Eq.…”

Section: Resultssupporting

confidence: 63%

“…The deceleration of the hydration fluctuations by the ligand very likely has its origin in the increased height of the vapor nucleation barrier at close ligand distances (16). Hydrodynamic deceleration has also been found for an approaching pair of model fullerenes (35). In turn, the ligand's dynamics intimately couples to the local solvent fluctuations as shown in Fig.…”

Section: Resultsmentioning

confidence: 76%

“…They investigated the interplay between HI and the free-energy landscape in the pair association kinetics of fullerenes and hydrophobic plates by explicit-water molecular dynamics (MD) simulations and diffusive approaches (35,36). Local friction was found to increase an order of magnitude due to HI, which slowed the assembly considerably by opposing the overall favorable free energy.…”

Section: Markovian Processmentioning

confidence: 99%

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Solvent fluctuations in hydrophobic cavity–ligand binding kinetics

Setny

Baron

Kekenes‐Huskey

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

155

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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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Section: Resultssupporting

confidence: 63%

Section: Resultsmentioning

confidence: 76%

Section: Markovian Processmentioning

confidence: 99%

See 1 more Smart Citation

Solvent fluctuations in hydrophobic cavity–ligand binding kinetics

Setny

Baron

Kekenes‐Huskey

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

155

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“…A crowded environment manifests small accessible volume fractions compared to bulk solutions, as well as long-range electrostatic and van der Waals (vdW) interactions between diffusers and obstacles, that together conspire to determine effective diffusion rates. 1,3,4 For such regimes, macroscopic models of hindered diffusion that reflect microscopic-scale phenomena are particularly insightful for understanding biological signaling. Particle-based methods such as Brownian dynamics (BD) and molecular dynamics simulations have traditionally been used to explore such interactions in crowded cellular environments (reviewed in Ref.…”

Section: Introductionmentioning

confidence: 99%

Predicting the influence of long-range molecular interactions on macroscopic-scale diffusion by homogenization of the Smoluchowski equation

Kekenes‐Huskey

Gillette

McCammon

2014

The Journal of Chemical Physics

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The macroscopic diffusion constant for a charged diffuser is in part dependent on (1) the volume excluded by solute "obstacles" and (2) long-range interactions between those obstacles and the diffuser. Increasing excluded volume reduces transport of the diffuser, while long-range interactions can either increase or decrease diffusivity, depending on the nature of the potential. We previously demonstrated [P. M. Kekenes-Huskey et al., Biophys. J. 105, 2130] using homogenization theory that the configuration of molecular-scale obstacles can both hinder diffusion and induce diffusional anisotropy for small ions. As the density of molecular obstacles increases, van der Waals (vdW) and electrostatic interactions between obstacle and a diffuser become significant and can strongly influence the latter's diffusivity, which was neglected in our original model. Here, we extend this methodology to include a fixed (time-independent) potential of mean force, through homogenization of the Smoluchowski equation. We consider the diffusion of ions in crowded, hydrophilic environments at physiological ionic strengths and find that electrostatic and vdW interactions can enhance or depress effective diffusion rates for attractive or repulsive forces, respectively. Additionally, we show that the observed diffusion rate may be reduced independent of non-specific electrostatic and vdW interactions by treating obstacles that exhibit specific binding interactions as "buffers" that absorb free diffusers. Finally, we demonstrate that effective diffusion rates are sensitive to distribution of surface charge on a globular protein, Troponin C, suggesting that the use of molecular structures with atomistic-scale resolution can account for electrostatic influences on substrate transport. This approach offers new insight into the influence of molecular-scale, long-range interactions on transport of charged species, particularly for diffusion-influenced signaling events occurring in crowded cellular environments.

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“…The hydrodynamic interactions quantified by the distance-dependent diffusion coefficient are also central to the theory and simulation of polymer dynamics, including protein folding simulations in implicit solvent, the hydrodynamic coupling in dense colloidal suspensions, and the function of nanomachines and bacterial flagella. 2,3 Pair diffusion therefore has attracted considerable attention from theoretical and simulation communities [4][5][6][7][8][9][10][11] in reflection of its fundamental and practical relevance, and as a means to test kinetic theory predictions. The studies of Haan, 4 Posch, Vesely, and Steele, 5 and Balucani et al 6 constitute early attempts to resolve at least average aspects of the position dependence of D(r) by simulation.…”

Section: Introductionmentioning

confidence: 99%

Pair diffusion, hydrodynamic interactions, and available volume in dense fluids

Mittal

Hummer

2012

The Journal of Chemical Physics

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We calculate the pair diffusion coefficient D(r) as a function of the distance r between two hard sphere particles in a dense monodisperse fluid. The distance-dependent pair diffusion coefficient describes the hydrodynamic interactions between particles in a fluid that are central to theories of polymer and colloid dynamics. We determine D(r) from the propagators (Green's functions) of particle pairs obtained from molecular dynamics simulations. At distances exceeding ∼3 molecular diameters, the calculated pair diffusion coefficients are in excellent agreement with predictions from exact macroscopic hydrodynamic theory for large Brownian particles suspended in a solvent bath, as well as the Oseen approximation. However, the asymptotic 1/r distance dependence of D(r) associated with hydrodynamic effects emerges only after the pair distance dynamics has been followed for relatively long times, indicating non-negligible memory effects in the pair diffusion at short times. Deviations of the calculated D(r) from the hydrodynamic models at short distances r reflect the underlying many-body fluid structure, and are found to be correlated to differences in the local available volume. The procedure used here to determine the pair diffusion coefficients can also be used for single-particle diffusion in confinement with spherical symmetry.

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Interplay between Hydrodynamics and the Free Energy Surface in the Assembly of Nanoscale Hydrophobes

Cited by 55 publications

References 71 publications

Solvent fluctuations in hydrophobic cavity–ligand binding kinetics

Solvent fluctuations in hydrophobic cavity–ligand binding kinetics

Predicting the influence of long-range molecular interactions on macroscopic-scale diffusion by homogenization of the Smoluchowski equation

Pair diffusion, hydrodynamic interactions, and available volume in dense fluids

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