Ž . Biophysical Chemistry 71 1998 199–204 Contributions of solvent–solvent hydrogen bonding and van der Waals interactions to the attraction between methane molecules in water Jeffrey A. Rank, David Baker ) Department of Biochemistry, UniÕersity of Washington, Seattle, WA, USA Received 7 November 1997; revised 7 January 1998; accepted 7 January 1998 Abstract The contribution of solvent–solvent hydrogen bonding and van der Waals interactions to the attraction between methane Ž . molecules in water was investigated by comparing the potential of mean force PMF between two methane molecules in TIP4P water to those in a series of related liquids in which the solvent–solvent interactions were progressively turned off while keeping the solvent–solute interactions unchanged. The magnitude of the attraction between methanes was not significantly changed when the hydrogen bonding interaction between solvent molecules was eliminated and the solvent was maintained in the liquid state by increasing either the pressure or the magnitude of the solvent–solvent van der Waals interaction. However, when solvent–solvent excluded volume interactions were eliminated, the methane molecules inter- acted no more strongly than in the gas phase. The results are consistent with the idea that the primary contribution of hydrogen bonding to the hydrophobic interaction is to keep water molecules in a liquid state; at constant density, packing interactions rather than hydrogen bonding appear to be critical as suggested by scaled particle theories of solvation. The overall shape of the PMF was, however, changed in the absence of hydrogen bonding, pointing to an influence of hydrogen bonding on the detailed form of the interactions between nonpolar solutes in water. The effects of correlations between the configurations sampled during the Monte Carlo procedure used in the free energy calculations on the estimation of errors was also characterized. q 1998 Elsevier Science B.V. All rights reserved. Keywords: Hydrophobic effect; Methane dimer; Potential of mean force 1. Introduction Although it is universally acknowledged that the hydrophobic effect plays a critical role in the stabi- lization of biological macromolecules, there is sur- prisingly little consensus on its physical origins; recent discussions have traced the hydrophobic effect ) Corresponding author. E-mail: dabaker@u.washington.edu w x to very different features of water 1–3 . A better understanding of hydrophobic interactions is essen- tial for understanding processes such as protein fold- ing which are largely driven by the clustering of w x nonpolar atoms in protein cores 4,5 . As the power of computers has increased, simula- tions of biological macromolecules have become an increasingly powerful research tool. Such simula- tions require a computationally tractable model of 0301-4622r98r$19.00 q 1998 Elsevier Science B.V. All rights reserved. Ž . PII S0301-4622 98 00103-3