Free energy, entropy, and enthalpy of a water molecule in various protein environments.

To examine the wide variety of cavities available to water molecules inside proteins, a model of the protein cavities is developed with the local environment treated at atomic detail and the nonlocal environment treated approximately. The cavities are then changed to vary in size and in the number of hydrogen bonds available to a water molecule inside the cavity. The free energy, entropy, and enthalpy change for the transfer of a water molecule to the cavity from the bulk liquid is calculated from thermodynamic integration. The results of the model are close to those of similar cavities calculated using the full protein and solvent environment. As the number of hydrogen bonds resulting from the addition of the water molecule increases, the free energy decreases, as the enthalpic gain of making a hydrogen bond outweighs the entropic cost. Changing the volume of the cavity has a smaller effect on the thermodynamics. Once the hydrogen bond contribution is taken into account, the volume dependence on DeltaG, DeltaS, and DeltaH is small and roughly the same for a hydrophobic cavity as a hydrophilic cavity.