How hydrophobic drying forces impact the kinetics of molecular recognition

Abstract

A model of protein-ligand binding kinetics, in which slow solvent dynamics results from hydrophobic drying transitions, is investigated. Molecular dynamics simulations show that solvent in the receptor pocket can fluctuate between wet and dry states with lifetimes in each state that are long enough for the extraction of a separable potential of mean force and wet-to-dry transitions. We present a diffusive surface hopping model that is represented by a 2D Markovian master equation. One dimension is the standard reaction coordinate, the ligand-pocket separation, and the other is the solvent state in the region between ligand and binding pocket which specifies whether it is wet or dry. In our model, the ligand diffuses on a dynamic free-energy surface which undergoes kinetic transitions between the wet and dry states. The model yields good agreement with results from explicit solvent molecular dynamics simulation and an improved description of the kinetics of hydrophobic assembly. Furthermore, it is consistent with a "non-Markovian Brownian theory" for the ligand-pocket separation coordinate alone.hydrophobicity | hydrodynamics | non-Markovian effects | dewetting transitions R ecent theoretical work has shown that the displacement of water by drug molecules is important in the thermodynamics and kinetics of ligand-enzyme binding (1-3). The kinetics of drug docking is a key metric for lead optimization (4). Presently, we explore the kinetic motifs of hydrophobic association on ligand binding. This is achieved by developing a simple model for hydrophobic association that is compared with explicit solvent molecular dynamics (MD) simulation.One of the signature features of hydrophobic assembly is the observation of a dewetting transition (5-9). Drying plays an important role in protein self-assembly and the behavior of nanoconfined water (10, 11). The present paper draws on our extensive work on the role of molecular-scale hydrodynamics in hydrophobic collapse (12, 13), where we showed that when the attraction between water and two associating nanoscale objects is weak, assembly proceeds via a drying transition in the intersolute region. This transition is characterized by large peaks in the relative translational friction coefficient that correspond to large and slow solvent fluctuations. The slow relaxation times exhibited by water undergoing dewetting transitions suggest that nonMarkovian effects may prove to be a crucial element in a full description of the assembly kinetics.We presently extend our earlier investigations to a model of a spherical ligand docking in a concave cavity. The model is similar to one investigated in a series of papers by McCammon and coworkers (14,15), but is altered to describe the assembly of a nanoscale ligand. This alteration facilitates the study of a largescale drying transition. We investigate molecular-scale hydrodynamic effects and the rate constants for binding and develop a theoretical framework to describe hydrophobic assembly. This theory couples the diffusive reaction coordi...

Pathways to dewetting in hydrophobic confinement

“…In particular, recent work has highlighted the importance of including the solvent coordinate, N, in describing the kinetics of hydrophobically driven collapse and assembly (49)(50)(51)59). Our results show that water density fluctuations stabilize nonclassical pathways, which reduce the barriers along the N coordinate, and should therefore enhance the kinetics of dewetting-mediated biophysical phenomena.…”

“…In particular, both simulations and theory have shown that the likelihood of observing low-density fluctuations adjacent to extended hydrophobic surfaces is enhanced relative to Gaussian statistics (13,31,(36)(37)(38)42). Further, the intricate coupling between enhanced solvent fluctuations and dewetting kinetics has been highlighted by both coarse-grained (45)(46)(47) and atomistic simulations (48)(49)(50)(51).…”

On the role of water density fluctuations in the inhibition of a proton channel

“…Current trends in drug design aim at exploiting the thermodynamics of waters trapped in protein binding pockets for lead design and optimization (83)(84)(85)(86)(87)(88)(89)(90). Hence, ligand scaffolds have been rationally designed for the purpose of displacing water molecules from druggable pockets, leading to the formation of thermodynamically favorable protein-ligand complexes (85).…”

Stochastic level-set variational implicit-solvent approach to solute-solvent interfacial fluctuations

“…Such a drying process, i.e., dewetting transition or capillary evaporation, has been found in experiment and computer simulations [24][25][26]28,30,[33][34][35][36][54][55][56] and is known to play a crucial role in many important biological processes, such as receptorligand binding. 3,32,[57][58][59] We apply our stochastic level-set method to study the dewetting transition in two hydrophobic systems: two parallel hydrophobic plates, and the synthetic host molecule cucurbit [7]uril (CB [7]). By using the deterministic level-set method developed in our previous works, 29,39,41,42,45,46 we are able to find multiple local minima with different initial guesses.…”