System Size Dependence of Hydration-Shell Occupancy and Its Implications for Assessing the Hydrophobic and Hydrophilic Contributions to Hydration

The occupancy distribution of water molecules in the first hydration shell around a solute is intimately connected with solvent density fluctuations and is of fundamental interest in understanding hydration. 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, emphasizing that the solvent density fluctuations are themselves dependent 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. The net hydration free energy benefits somewhat from the compensation of hydrophilic and hydrophobic contributions; nevertheless a large system appears necessary to describe correctly the balance of these contributions in the hydration of the macromolecule.