Molecular dynamics simulations employing umbrella sampling techniques have been used to calculate the potential of mean force (pmf) for the binding of a beta-D-glucopyranose molecule to a benzene molecule in aqueous solution, as a model for the binding of sugar substrates to phenylalanine residues in proteins. The interaction of these two molecules was found to be strongly affected by hydration, as expected, with their nonpolar faces pairing by hydrophobic association to minimize the exposure of apolar groups to water. The pmf for the approach of these molecules is oscillatory in character, with two primary low-energy minima separated by a high free energy barrier, and with the net binding energy being approximately 1.1 kcal/mol and the intervening barrier being almost 2 kcal/mol. A third, weaker minimum was observed between 11 and 12 Angstrom. The oscillatory nature of the pmf results from the successive removal of water layers between the two molecules as they approach one another.