The Mechanism of Hydrophobic Solvation Depends on Solute Radius

Abstract

We model the aqueous solvation of a nonpolar solute as a function of its radius. We use a simplified statistical mechanical model of water, the Mercedes Benz (MB) model, in NPT Monte Carlo simulations. This model has previously been shown to predict qualitatively the volume anomalies of pure water and the free energy, enthalpy, entropy, heat capacity, and volume change for inserting a nonpolar solute into water. We find a very different mechanism for the aqueous solvation of large nonpolar solutes (much larger than a water) than for smaller solutes. Small solute transfer involves a large hydrophobic heat capacity; its disaffinity for cold water (room temperature or below) is due to the ordering of the neighboring waters (entropic), while its disaffinity for hot water is due to the breaking of hydrogen bonds among the neighboring waters (enthalpic). In contrast, transferring large nonpolar solutes into water involves no such large changes in heat capacity or entropy. In this regard, large nonpolar solutes are not “hydrophobic”; their solvation follows classical regular solution theory. Putting a large nonpolar surface into water breaks hydrogen bonds at all temperatures. Therefore, the traditional “iceberg” model that first-shell water structure melts out with temperature should not apply to large solutes. These results also explain why the free energy of creating an oil/water interface (75 cal Å-2 mol-1) is greater than threefold for small molecule transfers (25 cal Å-2 mol-1). A key conclusion is that hydrophobicity depends not only on the surface area of a solute but also on its shape and curvature.

Signature of hydrophobic hydration in a single polymer

“…In contrast to the temperature dependence of macroscopic interfacial free energy, ΔG hyd for a hydrophobic solute increases at low temperature, reaches a maximum and decreases at high temperature. This temperature dependence has been observed for small hydrocarbon molecules (36), and has been reproduced by many theoretical studies (19,21,23,28). This anomalous increase in the hydration free energy before the turnover point is believed to originate from the lowered entropy of water molecules adjacent to the small hydrophobic molecules, as the degrees of freedom of these water molecules are reduced by the formation of more ordered, dynamic structures.…”

“…Once the particle size is greater than a few nanometers, its hydration free energy follows macroscopic interfacial thermodynamics, which monotonically decreases as temperature rises. Theories on small particle hydration have shown that as the particle size increases, the temperature at which ΔG hyd is maximized will shift lower, providing a smooth transition between the temperature dependence of ΔG hyd from small to large solute (21,23,28). To examine this effect, two other hydrophobic polymers with identical backbones but side chains of different sizes were used: PtBS and PVBP with calculated monomer sizes (backbone + side chain) of approximately 9.5 Å and approximately 11.4 Å, respectively.…”

“…However, it was argued that the correction to the effective surface tension to maintain the correlation between ΔG hyd and SASA at small length scales lacked a clear physical meaning (16). Instead of depending on a scaling relation with SASA, theories and simulations were developed predicting that ΔG hyd has nontrivial size dependence: Below approximately 1 nm radius, ΔG hyd of a spherical solute scales roughly with the solute volume; whereas above this value, ΔG hyd scales with SASA and asymptotically approaches the behavior described by macroscopic interfacial thermodynamics (6,(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28). These treatments correctly predict the trend for the temperature dependence of ΔG hyd for small molecules.…”

Structure-Based Identification of Small Molecule Binding Sites Using a Free Energy Model

“…The curvature approach we use is a simplified representation of desolvation that appears to capture the role of topology. 13 Because the organization of waters is affected by the surrounding surface topology in addition to the individual surface piece, we use the continuous surface within 3.0 Å of the center of the surface piece in calculating the curvature. For the studies shown in this paper, we used a γ(∞) ) 47.5 cal/mol/Å 2 and required γ(r) to be in the range of 15-140 cal/mol/Å 2 in order to limit affinity contributions from any given node.…”

Weak Interactions in Protein Folding: Hydrophobic Free Energy, van der Waals Interactions, Peptide Hydrogen Bonds, and Peptide Solvation

“…Chandler [37] explains that these two different outcomes, which depend on solute size, arise naturally from the Hbonding properties of water, because the sheath of water molecules that surrounds a nonpolar solute remains fully H-bonded when the solute is sufficiently small but not when the solute radius exceeds a critical value. Southall and Dill [41] find that a highly simplified model of the water molecule (the ''Mercedes-Benz'' model), which reproduces several remarkable properties of water, also predicts such a transition from microscopic to macroscopic solvation behavior.…”