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
Abstract:
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.