To investigate the cooperativity of hydrophobic
interactions, the potential of mean force of two- and three-molecule
methane clusters in water was determined by molecular dynamics
simulations using two methods: umbrella-sampling with the
weighted histogram analysis method and thermodynamic integration.
Two water models, TIP3P and TIP4P, were used, while each
methane molecule was modeled as a united atom. It was found
that the three-body potential of mean force is not additive,
i.e., it cannot be calculated as a sum of two-body contributions,
but requires an additional three-body cooperative
term. The cooperative term, which amounts to only about
10% of the total hydrophobic association free energy, was
found to increase the strength of hydrophobic association;
this finding differs from the results of earlier Monte
Carlo studies with the free energy perturbation method
of Rank and Baker (1997). As in the work of Rank and Baker,
the solvent contribution to the potential of mean force
was found to be well approximated by the molecular surface
of two methane molecules. Moreover, we also found that
the cooperative term is well represented by the difference
between the molecular surface of the three-methane cluster
and those of all three pairs of methane molecules. In addition,
it was found that, while there is a cooperative contribution
to the hydrophobic association free energy albeit a small
one, the errors associated with the use of pairwise potentials
are comparable to or larger than this contribution.