Enthalpy-entropy contributions to the potential of mean force of nanoscopic hydrophobic solutes

Entropic and enthalpic contributions to the hydrophobic interaction between nanoscopic hydrophobic solutes, modeled as graphene plates in water, have been calculated using molecular dynamics simulations in the isothermal-isobaric (NPT) ensemble with free energy perturbation methodology. We find the stabilizing contribution to the free energy of association (contact pair formation) to be the favorable entropic part, the enthalpic contribution being highly unfavorable. The desolvation barrier is dominated by the unfavorable enthalpic contribution, despite a fairly large favorable entropic compensation. The enthalpic contributions, incorporating the Lennard-Jones solute-solvent terms, largely determine the stability of the solvent separated configuration. We decompose the enthalpy into a direct solute-solute term, the solute-solvent interactions, and the remainder that contains pressure-volume work as well as contributions due to solvent reorganization. The enthalpic contribution due to changes in water-water interactions arising from solvent reorganization around the solute molecules is shown to have major contribution in the solvent induced enthalpy change.