Small and large hydrophobic solutes exhibit remarkably different hydration thermodynamics. Small solutes are accommodated in water with minor perturbations to water structure, and their hydration is captured accurately by theories that describe density fluctuations in pure water. In contrast, hydration of large solutes is accompanied by dewetting of their surfaces and requires a macroscopic thermodynamic description. A unified theoretical description of these lengthscale dependencies was presented by Lum, Chandler, and Weeks [(1999) J. Phys. Chem. B 103, 4570 -4577]. Here, we use molecular simulations to study lengthscale-dependent hydrophobic hydration under various thermodynamic conditions. We show that the hydration of small and large solutes displays disparate dependencies on thermodynamic variables, including pressure, temperature, and additive concentration. Understanding these dependencies allows manipulation of the small-tolarge crossover lengthscale, which is nanoscopic under ambient conditions. Specifically, applying hydrostatic tension or adding ethanol decreases the crossover length to molecular sizes, making it accessible to atomistic simulations. With detailed temperaturedependent studies, we further demonstrate that hydration thermodynamics changes gradually from entropic to enthalpic near the crossover. The nanoscopic lengthscale of the crossover and its sensitivity to thermodynamic variables imply that quantitative modeling of biomolecular self-assembly in aqueous solutions requires elements of both molecular and macroscopic hydration physics. We also show that the small-to-large crossover is directly related to the Egelstaff-Widom lengthscale, the product of surface tension and isothermal compressibility, which is another fundamental lengthscale in liquids. molecular dynamics ͉ salt and additive effects ͉ density fluctuations ͉ nonpolar solvation B iological self-assembly processes in aqueous solutions are driven by water-mediated interactions between constituents taking part in the assembly. Of these, hydrophobic interactions have received particular attention because of their relevance to protein folding and interactions, micelle and membrane formation, and molecular recognition (1-5). Theoretical work in this direction has been focused on the modeling of primitive hydrophobic phenomena, such as hydration and association of small hydrophobic particles in water (6-13). However, biological assembly occurs over a spectrum of lengthscales from that of an amino acid to proteins and larger. Naturally, fundamental understanding of the lengthscale dependence of hydration and association of hydrophobic solutes in water will be relevant to the quantitative modeling of realistic macromolecular processes (14,15).Small hydrophobic solutes can be accommodated into the open hydrogen-bonded network of liquid water without significant perturbations. Indeed, theories that model density fluctuations over small lengthscales in pure water provide a quantitative description of the hydration thermodynamics of small...

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.

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