Hydrophobicity of proteins and nanostructured solutes is governed by topographical and chemical context

Abstract

Hydrophobic interactions drive many important biomolecular selfassembly phenomena. However, characterizing hydrophobicity at the nanoscale has remained a challenge due to its nontrivial dependence on the chemistry and topography of biomolecular surfaces. Here we use molecular simulations coupled with enhanced sampling methods to systematically displace water molecules from the hydration shells of nanostructured solutes and calculate the free energetics of interfacial water density fluctuations, which quantify the extent of solute-water adhesion, and therefore solute hydrophobicity. In particular, we characterize the hydrophobicity of curved graphene sheets, self-assembled monolayers (SAMs) with chemical patterns, and mutants of the protein hydrophobin-II. We find that water density fluctuations are enhanced near concave nonpolar surfaces compared with those near flat or convex ones, suggesting that concave surfaces are more hydrophobic. We also find that patterned SAMs and protein mutants, having the same number of nonpolar and polar sites but different geometrical arrangements, can display significantly different strengths of adhesion with water. Specifically, hydroxyl groups reduce the hydrophobicity of methyl-terminated SAMs most effectively not when they are clustered together but when they are separated by one methyl group. Hydrophobin-II mutants show that a charged amino acid reduces the hydrophobicity of a large nonpolar patch when placed at its center, rather than at its edge. Our results highlight the power of water density fluctuations-based measures to characterize the hydrophobicity of nanoscale surfaces and caution against the use of additive approximations, such as the commonly used surface area models or hydropathy scales for characterizing biomolecular hydrophobicity and the associated driving forces of assembly.nanotube | curvature | chemical pattern | hydrophilicity | graphene H ydrophobic interactions drive many important biological and colloidal self-assembly processes (1-6). During such assembly, the hydration shells of the associating solutes are disrupted, replacing hydrophobic-water contacts with hydrophobic-hydrophobic ones. Characterizing how strongly water adheres to a given solute is, therefore, directly relevant to the strength of hydrophobic interactions between solutes. Macroscopically, surface-water adhesion is quantified by measuring the water droplet contact angle on a surface. However, such characterization does not translate usefully to proteins and other nanoscale solutes. Indeed, characterizing how strongly or weakly a protein surface or a specific patch on it adheres to water (i.e., its hydrophobicity) is incredibly challenging and has necessitated the use of simplifying assumptions.To this end, simple surface area (SA) models have been used to estimate the driving force for assembly, ∆G = γ∆A, where ∆A is the nonpolar SA buried upon assembly and γ is an appropriate surface tension (7-9). However, the value of γ used in popular models is nearly an order of magnitude lower t...

Characterizing Solvent Density Fluctuations in Dynamical Observation Volumes

“…Our findings are consistent with those of Pettitt and co-workers, who showed that the conformation of alkane chains and peptides can influence their hydration free energies substantially [66][67][68]. Our results also lend further support to the notion that surface-area models, which are commonly used to estimate the driving force of hydrophobic assembly, but are incapable of capturing subtle but important differences between the rigid and flexible solutes, are not appropriate for a quantitative treatment of hydrophobic hydration and interactions [66,69].…”

Protein Hydration Waters Are Susceptible to Unfavorable Perturbations

“…19,22,[26][27][28][29][30][31][32][33][34][35] In contrast with simple hydrophobic or hydrophilic surfaces, proteins display nanoscopic chemical and topographical patterns, which influence their interactions with water in nontrivial ways. 20,[36][37][38][39][40][41][42][43][44][45][46] By interrogating how protein hydration waters respond to an unfavorable potential, here we find that the hydration shells of diverse proteins are also situated at the edge of a dewetting transition. Such a resemblance of protein hydration shells to extended hydrophobic surfaces appears to arise from the fact that -even for protein surfaces that are enriched in polar and charged residues -roughly half the surface consists of hydrophobic atoms.…”

Disassembling solvation free energies into local contributions—Toward a microscopic understanding of solvation processes

“…[11][12][13] Common implicit solvation models describe water-mediated interactions based on a context-independent classification of molecular surfaces as either hydrophobic or hydrophilic. While such approaches provide qualitative insights, experiments 14 and explicit solvent simulations [15][16][17] show that the atomistic detail of molecular surfaces significantly affects interactions with an aqueous solvent. This is particularly the case in the context of chemically and topologically heterogeneous surfaces of biomolecules, where microscopic features ultimately determine whether solvent/water-mediated interactions between two interfaces are attractive or repulsive.…”

“…Useful insights into local hydrophobic or hydrophilic properties of a molecular surface can be obtained from local water density fluctuations that are easily analyzed in explicit solvent computer simulations. [15][16][17][18] The latter are increased in the case of hydrophobic surfaces, while attractive interactions of water with a polar surface suppress fluctuations. 15 As an alternative to the analysis of density fluctuations, explicit solvent simulations in the presence of small hydrophobic probe particles show directly where attractive water-mediated interactions result in an increase in the local concentration of the probe particles.…”