Hydration of Cavities in Proteins: A Molecular Dynamics Approach

Rebecca C. Wade, Michael H. Mazor, J. Andrew McCammon, and Florante A. Quiocho

Department of Chemistry, University of Houston, Houston, Texas 77204-5641
Howard Hughes Medical Institute, Departments of Biochemistry and of Physiology and Molecular Biophysics
Baylor College of Medicine, Houston, Texas 77030


Internal water molecules play an important role in the structure and function of proteins. The ability to predict their structural and thermodynamic properties would be of value in, e.g., the design of ligands, such as drugs; the study of protein-protein interfaces and protein folding; and the location of water molecules in protein structures solved at low resolution by X-ray crystallography.
Numerous theoretical methods have been used to study protein hydration. Here, we propose the application of statistical thermodynamic perturbation and integration techniques to determine the energetic and structural properties of internal water molecules in proteins. These techniques have previously been used for computing the excess chemical potential of water and the relative free energies of hydration of small molecules and ions . The excess chemical potential of water is constant throughout a system at equilibrium and is given by the free energy change associated with hydrating any given position in bulk solvent with one water molecule. Protein cavities will tend to be occupied by water if the corresponding free energy of hydration is less than that of the bulk solvent. This free energy has been computed for two representative cavities in a protein and found to be consistent with their experimentally observed occupancies.

J. Am. Chem. Soc. (1990) 112, 7057-7059.