Can cooperativity in hydrophobic association be reproduced correctly by implicit solvation models?

The potential of mean force (PMF) of the hydrophobic association of pairs and triplets of nonpolar solute molecules with various sizes and strengths of van der Waals interactions has been studied by means of umbrella-sampling molecular-dynamic simulations combined with the weighted-histogram analysis method. The TIP3P water model was used in these computations. It was found that the distance dependence of the PMF, including the three-body (cooperative) contribution, is described qualitatively correctly by the variation of either the molecular surface area or the excluded solvation-shell molecular volume with the distance between the solute molecules, while the solvent-accessible surface and the hydration-shell models, which are commonly used in mean-field solvation approaches, give an incorrect distance dependence and the wrong sign of the cooperative contribution. The cooperative contribution to the PMF increases the strength of hydrophobic interactions and increases with the size of the solute. (C) 2002 Wiley Periodicals, Inc.