Inferring the hydrophobic interaction from the properties of neat water.

The present paper by Hummer et al. (1), building on previous developments in scaled-particle theory (2) and information theory (3-6) and using molecular simulations to test theoretical ideas, shows how one can predict the free energies of the hydrophobic hydration and the hydrophobic interaction of solutes composed of hard spheres from an analysis of spontaneous cavity formation in neat liquid water. Hummer et al. (1) dramatically extend ideas from scaled particle theory and demonstrate a simple, highly efficient approach to computing solution thermodynamic properties from either simulation or theory. This paper is a commentary on the background and the ideas presented in the paper by Hummer et al. (1). The whole field of condensed matter chemistry has been greatly advanced by the power of computer simulation (7). It wasn't until the second half of the 1960s that the first molecular dynamics simulations were performed on simple molecular liquids (8, 9). Molecular simulations provide clear data for theories of liquids, allow direct tests of theoretical approximations, and often point the way to better simplifying approximations to be made in analytical theories. The present paper uses both theory and simulation data to find simple answers to an apparently complicated question. It is difficult to imagine this kind of simplicity without the extensive development of simulation techniques that have gone before. Water has been studied with simple force fields (10) since the 1970s, and the solubility of inert gases in water has been modeled by treating the inert gas atom as a hard sphere that excludes the center of the water molecule from a region around it (11). Studies of such systems give insight into "hydrophobic hydration," the reorganization of water structure around the hard sphere, as well as the free energy of hydration of the sphere. More realistic solute-solvent interactions can then be treated by statistical perturbation (12) theory using the hard sphere reference system. Such an approach was pioneered by Pratt and Chandler (11). When two hard spheres of typeA are dissolved in water, there is a solvent-induced force driving the spheres into association. This is the so-called "hydrophobic interaction." The free energy change, W(R), on bringing the two spheres together from infinity to a separation R, called the potential of mean force (pmf), is related to the radial distribution function of the two spheres, gAA(R), through the relation (12, 13)