Molecular dynamics free energy calculations to assess the possibility of water existence in protein nonpolar cavities

Oikawa, Masataka; Yonetani, Yoshiteru

Are protein nonpolar cavities filled with water molecules ? Though many experimental and theoretical investigations have been done, particularly for the nonpolar cavity of IL-1, the results are still conflicting. To study this problem from the thermodynamic point of view, we calculated hydration free energies of four protein nonpolar cavities by means of the molecular dynamics thermodynamic integration method. Besides the IL-1 cavity, we selected the three largest nonpolar cavities from the structural database, in view of the simulation result of Vaitheeswaran et al. [Proc. Natl. Acad. Sci. (2004)] showing that larger nonpolar cavities are more expected to be hydrated. The calculated free energy changes were all positive; hydration of the nonpolar cavities was energetically unfavorable for all four cases. Because hydration of smaller cavities should happen more rarely, we conclude that existing protein nonpolar cavities are not likely to be hydrated. Although a possibility remains for much larger nonpolar cavities, such cases are not found experimentally. We present a hypothesis to explain this: hydrated nonpolar cavities are quite unstable and the conformation could not be maintained.