[Effect of buried bound water in protein-ligand association processes]

The role of water molecules on the protein-ligand interface during macromolecular association has been determined. The free energy of association of insulin has been calculated by the molecular mechanics method using the continuum Poisson-Boltzman models. The previously developed scheme of the decomposition of association free energy onto contributions from individual interactions has been used to calculate intermolecular interactions, the solvation free energy, and the entropies of the process of macromolecular association. An analysis of the calculated oscillation spectra indicated that the presence of water molecules on the protein-protein interface promotes an increase in the contribution of vibration entropy to the free energy of association due to the enhancement of the flexibility of the complex. It was shown that water molecules involved in the formation of protein-water-ligand hydrogen bond change the balance of forces in the system.