Quantifying the Entropy of Binding for Water Molecules in Protein Cavities by Computing Correlations

• Published in: Biophysical journal Vol. 108; no. 4; pp. 928 - 936
• Main Author: Huggins, David J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 17.02.2015; Biophysical Society; The Biophysical Society
• Subjects: Binding sites; Correlation analysis; Crystals; Entropy; Hydrophobic and Hydrophilic Interactions; Molecular Dynamics Simulation; Molecules; Protein Binding; Protein Conformation; Proteins; Proteins - chemistry; Proteins - metabolism; Proteins and Nucleic Acids; Structural analysis; Water
• ISSN: 0006-3495; 1542-0086; 1542-0086
• DOI: 10.1016/j.bpj.2014.12.035

Protein structural analysis demonstrates that water molecules are commonly found in the internal cavities of proteins. Analysis of experimental data on the entropies of inorganic crystals suggests that the entropic cost of transferring such a water molecule to a protein cavity will not typically be greater than 7.0 cal/mol/K per water molecule, corresponding to a contribution of approximately +2.0 kcal/mol to the free energy. In this study, we employ the statistical mechanical method of inhomogeneous fluid solvation theory to quantify the enthalpic and entropic contributions of individual water molecules in 19 protein cavities across five different proteins. We utilize information theory to develop a rigorous estimate of the total two-particle entropy, yielding a complete framework to calculate hydration free energies. We show that predictions from inhomogeneous fluid solvation theory are in excellent agreement with predictions from free energy perturbation (FEP) and that these predictions are consistent with experimental estimates. However, the results suggest that water molecules in protein cavities containing charged residues may be subject to entropy changes that contribute more than +2.0 kcal/mol to the free energy. In all cases, these unfavorable entropy changes are predicted to be dominated by highly favorable enthalpy changes. These findings are relevant to the study of bridging water molecules at protein-protein interfaces as well as in complexes with cognate ligands and small-molecule inhibitors.