Introduction

It can be easily explained why charged or polar molecules dissolve much better in water than in non-polar organic liquids, such as hexane, ``but even professional chemists have difficulty accounting for why non-polar liquids outdo water in dissolving electrically neutral gas molecules such as methane.'' [1] The poor solubility of non-polar gases in water is only the simplest example of the hydrophobic effect. Among other, more complex, and certainly much more important, phenomena in which the hydrophobic effect plays an important role are the assembly of micelles and bilayer membranes, the folding, aggregation and cellular segregation of proteins and the delivery of drugs to their targets. [2, 3, 4, 5, 6]

The hydrophobic effect exhibits characteristics that distinguish it from other solvent effects. In contrast to hydrophilic solvation, which is enthalpic in nature, hydrophobic solvation is dominated by entropic interactions and characterized by a large negative heat capacity change. The hydrophobic effect manifests itself by unusual temperature dependencies; for example, the solubilities of non-polar solutes in water often decrease with increasing temperature and some proteins undergo denaturation upon cooling. [7] These special properties, which have no known counterparts in organic solvents, are assumed to result from the structure of liquid water. In line with the entropic nature of the hydrophobic effect, several bulk or collective properties of water, such as the packing of water molecules, the existence of hydrogen bond networks and the low compressibility of the liquid, have been proposed as relevant, but their relative importance is still not well known.

A wide variety of approaches have been used to characterize and explain the hydrophobic effect. Experimental methods have provided descriptions and fundamental thermodynamic data for many hydrophobic phenomena. [8, 5] These, in turn, have been used to develop empirical models for predicting such quantities as hydrophobic solubilities or hydrophobic contributions to protein folding. [9, 10, 11] The first attempts to explain the hydrophobic effect at a molecular level were made using analytical theories. [12, 13, 14] The latest arrival were computer simulation methods, which were initially used to reproduce measured quantities characteristic of simple hydrophobic phenomena and to provide a microscopic description of the solvent around hydrophobic species. [15, 16, 17] Only recently, these methods were applied to determine what factors are responsible for the hydrophobic effect in its different forms. [18, 19, 20, 21, , 23, 24]

One very fruitful approach to the theory of hydrophobicity is to analyze, by the means of computer simulations, the statistics of transient cavities in water and other molecular liquids. This brief overview is devoted to this topic. After presenting the fundamentals of the theory, the main results on the distributions of atomic-sized cavities are summarized and discussed in terms of the nature of the hydrophobic effect. This is followed by a description of an information theory model of the hydrophobic effect which is applicable to a significantly broader range of non-polar solutes.