Application of inhomogeneous fluid solvation theory to model the distribution and thermodynamics of water molecules around biomolecules

The structures of biomolecules and the strengths of association between them depend critically on interactions with water molecules. Thus, understanding these interactions is a prerequisite for understanding the structure and function of all biomolecules. Inhomogeneous fluid solvation theory provides a framework to derive thermodynamic properties of individual water molecules from a statistical mechanical analysis. In this work, two biomolecules are analysed to probe the distribution and thermodynamics of surrounding water molecules. The great majority of hydration sites are predicted to contribute favourably to the total free energy with respect to bulk water, though hydration sites close to non-polar regions of the solute do not contribute significantly. Analysis of a biomolecule with a positively and negatively charged functional group predicts that a charged species perturbs the free energy of water molecules to a distance of approximately 6.0 angstrom. Interestingly, short simulations are found to provide converged predictions if samples are taken with sufficient frequency, a finding that has the potential to significantly reduce the required computational cost of such analysis. In addition, the predicted thermodynamic properties of hydration sites with the potential for direct hydrogen bonding interactions are found to disagree significantly for two different water models. This study provides important information on how inhomogeneous fluid solvation theory can be employed to understand the structures and intermolecular interactions of biomolecules.