The packing and orientation of water molecules in the vicinity of solutes strongly influence the solute hydration thermodynamics in aqueous solutions. Here we study the charge density dependent hydration of a broad range of spherical monovalent ionic solutes (with solute diameters from approximately 0.4 nm to 1.7 nm) through molecular dynamics simulations in the simple point charge model of water. Consistent with previous experimental and theoretical studies, we observe a distinct asymmetry in the structure and thermodynamics of hydration of ions. In particular, the free energy of hydration of negative ions is more favorable than that of positive ions of the same size. This asymmetry persists over the entire range of solute sizes and cannot be captured by a continuum description of the solvent. The favorable hydration of negative ions arises primarily from the asymmetric charge distribution in the water molecule itself, and is reflected in (i) a small positive electrostatic potential at the center of a neutral solute, and (ii) clear structural (packing and orientation) differences in the hydration shell of positive and negative ions. While the asymmetry arising from the positive potential can be quantified in a straightforward manner, that arising from the structural differences in the fully charged states is difficult to quantify. The structural differences are highest for the small ions and diminish with increasing ion size, converging to hydrophobiclike hydration structure for the largest ions studied here. We discuss semiempirical measures following Latimer, Pitzer, and Slansky [J. Chem. Phys. 7, 108 (1939)] that account for these structural differences through a shift in the ion radius. We find that these two contributions account completely for the asymmetry of hydration of positive and negative ions over the entire range of ion sizes studied here. We also present preliminary calculations of the dependence of ion hydration asymmetry on the choice of water model that demonstrate its sensitivity to the details of ion-water interactions.

We report results on the pressure effects on hydrophobic interactions obtained from molecular dynamics simulations of aqueous solutions of methanes in water. A wide range of pressures that is relevant to pressure denaturation of proteins is investigated. The characteristic features of water-mediated interactions between hydrophobic solutes are found to be pressure-dependent. In particular, with increasing pressure we find that (1) the solvent-separated configurations in the solute-solute potential of mean force (PMF) are stabilized with respect to the contact configurations; (2) the desolvation barrier increases monotonically with respect to both contact and solvent-separated configurations; (3) the locations of the minima and the barrier move toward shorter separations; and (4) pressure effects are considerably amplified for larger hydrophobic solutes. Together, these observations lend strong support to the picture of the pressure denaturation process proposed previously by Hummer et al. (Proc. Natl. Acad. Sci. U.S.A. 1998, 95, 1552): with increasing pressure, the transfer of water into protein interior becomes key to the pressure denaturation process, leading to the dissociation of close hydrophobic contacts and subsequent swelling of the hydrophobic protein interior through insertions of water molecules. The pressure dependence of the PMF between larger hydrophobic solutes shows that pressure effects on the interaction between hydrophobic amino acids may be considerably amplified compared to those on the methane-methane PMF.

We present results from extensive molecular dynamics simulations of collapse transitions of hydrophobic polymers in explicit water focused on understanding effects of lengthscale of the hydrophobic surface and of attractive interactions on folding. Hydrophobic polymers display parabolic, protein-like, temperature-dependent free energy of unfolding. Folded states of small attractive polymers are marginally stable at 300 K and can be unfolded by heating or cooling. Increasing the lengthscale or decreasing the polymerwater attractions stabilizes folded states significantly, the former dominated by the hydration contribution. That hydration contribution can be described by the surface tension model, ⌬G ‫؍‬ ␥(T)⌬A, where the surface tension, ␥, is lengthscale-dependent and decreases monotonically with temperature. The resulting variation of the hydration entropy with polymer lengthscale is consistent with theoretical predictions of Huang and Chandler [Huang DM, Chandler D (2000) Proc Natl Acad Sci USA 97:8324 -8327] that explain the blurring of entropy convergence observed in protein folding thermodynamics. Analysis of water structure shows that the polymer-water hydrophobic interface is soft and weakly dewetted, and is characterized by enhanced interfacial density fluctuations. Formation of this interface, which induces polymer folding, is strongly opposed by enthalpy and favored by entropy, similar to the vapor-liquid interface.dewetting ͉ folding ͉ hydration entropy ͉ hydrophobic hydration ͉ hydrophobic interaction H ydrophobic interactions are one of the major contributors to biological self-assembly in solution, including protein folding and aggregation, micelle and membrane formation, and biomolecular recognition (1-5). Recent work in this area has focused on the lengthscale dependencies of hydrophobic hydration and interactions (4,(6)(7)(8)(9). In particular, a recent theory by Lum, Chandler, and Weeks (6) highlighted the different physical mechanisms of solvation of small and large hydrophobic solutes in water. Small solutes are accommodated in water through molecular-scale density fluctuations (10, 11), whereas solvation of larger solutes requires formation of an interface similar to that between a liquid and a vapor (4,6,12). This change in physics is also reflected in thermodynamic (entropy vs. enthalpy dominated hydration) (9) and structural (wetting vs. dewetting of the solute surface) (4, 12, 13) aspects of hydration. Similarly, interactions between larger hydrophobic solutes in water (14-18) are characteristically distinct from those between their molecular counterparts (19,20).The differences between the hydration and interactions of small and large solutes characterize many-body effects in hydrophobic phenomena. Effects of similar origin are also at work in association of small hydrophobic solutes into a larger aggregate (21,22) and are quantified by the n-particle potential of mean force (PMF) (23-26). For n Ͼ 3, however, the dimensionality of the system makes calculations of n-particle PMFs computa...

Salting-out of hydrophobic solutes in aqueous salt solutions and their relevance to salt effects on biophysical phenomena are now well appreciated. Although salt effects on hydrophobic transfer have been well studied, to our knowledge, no quantitative molecular simulation study of salt-induced strengthening of hydrophobic interactions has yet been reported. Here we present quantitative characterization of salt-induced strengthening of hydrophobic interactions at the molecular and nanoscopic length scales through molecular dynamics simulations. Specifically, we quantify the effect of NaCl on the potential of mean force between molecular hydrophobic solutes (methanes) and on conformational equilibria of a 25-mer hydrophobic polymer that efficiently samples ensembles of compact and extended states in water. In both cases, we observe relative stabilization of compact conformations that is accompanied by a clear depletion of salt density (preferential exclusion) and a slight enhancement of water density (preferential hydration) in the solute vicinity. We show that the structural details of salt exclusion can be related to the salt-induced free energy changes using preferential interaction coefficients. We also test the applicability of surface-area-based models to describe the salt-induced free energy changes. These models provide a useful empirical description that can be used to predict the effects of salt on conformational equilibria of hydrophobic solutes. However, we find that the effective increase in the surface tension of the solute-aqueous solution interface depends on the type and concentration of salt as well as the length-scale (i.e., molecular vs nanoscopic) of the conformational change. These calculations underscore the utility of simulation studies to connect quantitatively structural details at the molecular level (described by preferential hydration/exclusion) to macroscopic solvation thermodynamics. The hydrophobic polymer also provides a useful model for studies of effect of thermodynamic variables (P, T, salt/additives) on many-body hydrophobic interactions at nanometer length scales.