Pressure Effects on Protein Hydration Water Thermodynamics

In this molecular dynamics simulation study, we analyze the impact of increasing hydrostatic pressure on the solvation of protein surfaces. Apart from the increasing volume work required for the formation of the protein solute cavity at high hydrostatic pressures, no significant additional trend is observed for solvation free energy contributions due to the protein-water interactions analyzed here. The latter is the result of approximately canceling pressure-induced changes of enthalpic and entropic solvation free energy contributions, which can be traced back to changes in the hydration of hydrophilic and hydrophobic groups of the protein. The 3D-2PT analysis used here allows for the visualization of local solvation free energy contributions in three dimensions with high spatial resolution. Local solvation free energy contributions per water molecule at hydrophobic surfaces are small but mainly favorable for transfer processes from the gas phase. This does not change considerably with increasing pressure, while the number of hydrating water molecules increases due to increased packing of the hydration shell. The number of hydrating water molecules also increases for hydrophilic protein surfaces, but solvation contributions per water molecule become less favorable with pressure in this case. As a consequence, contributions to the total solvation free energy from interactions between water molecules and hydrophobic surfaces become increasingly relevant at high hydrostatic pressures. Our results provide novel insights into solvent-mediated contributions to the thermodynamic driving force of pressure denaturation of proteins.