Conformational free energies of butane, pentane, and hexane in water are calculated from molecular simulations with explicit waters and from a simple molecular theory in which the local hydration structure is estimated based on a proximity approximation. This proximity approximation uses only the two nearest carbon atoms on the alkane to predict the local water density at a given point in space. Conformational free energies of hydration are subsequently calculated using a free energy perturbation method. Quantitative agreement is found between the free energies obtained from simulations and theory. Moreover, free energy calculations using this proximity approximation are approximately four orders of magnitude faster than those based on explicit water simulations. Our results demonstrate the accuracy and utility of the proximity approximation for predicting water structure as the basis for a quantitative description of n-alkane conformational equilibria in water. In addition, the proximity approximation provides a molecular foundation for extending predictions of water structure and hydration thermodynamic properties of simple hydrophobic solutes to larger clusters or assemblies of hydrophobic solutes.
Bibliographical noteFunding Information:
We thank Angel E. García and Lawrence R. Pratt for numerous fruitful discussions over the years. Financial support from the National Aeronautics and Space Administration (NAG3-1954), the National Science Foundation (grant Nos. BES-9210401 and BES-9510420), the U.S. Department of Energy (W-7405-ENG-36), a National Science Foundation Fellowship for H.S.A. (GER-9253850), and a Los Alamos National Laboratory Director's Postdoctoral Fellowship for S.G. is gratefully acknowledged.