  The free energies to evacuate the first hydration shell around a solute and a
cavity defined by the first hydration shell depend on the system size. This
observation interpreted within the quasichemical theory shows that both the
hydrophilic and the hydrophobic contributions to hydration depend on the system
size, decreasing with increasing system size. Although the net hydration free
energy benefits somewhat from the balancing of hydrophilic and hydrophobic
contributions, a large system still appears necessary to describe the effect of
the solvent on the macromolecule.
