Electrostatic contributions to heat capacity changes and an analysis of thermal hysteresis protein hydration using the random network model

The structure and activity of proteins and nucleic acids are a direct consequence of the influence of water, their principal solvent. Although it is a small and deceptively simple molecule, our understanding of water and its effect on biomolecules remains limited. Significant heat capacity changes (ΔCp), which often accompany folding and binding reactions, are frequently used to analyze contributions from polar and apolar hydration. The first half of this work details a direct study of the effect of strong electrostatic interactions in DNA-drug binding reactions. Current models, based on solvent-accessible surface area (ASA) analyses, cannot accurately account for the heat capacity changes observed in these systems. We employ finite-difference Poisson-Boltzmann methods (FDPB) to determine the contribution of electrostatic interactions to ΔCp. Our results show that the ΔCp associated with electrostatics is small. The other portion of this work describes our efforts to understand the hydration of proteins. To do this, we use a model of water that interprets heat capacity changes in terms of the solute-induced structural reorganization of water-water hydrogen bonds. This model, derived from explicit-water simulations and a thermodynamic model of water, has been successful in reproducing both the sign and magnitude of ΔC p for many small solutes. Here, we refine our technique to increase agreement with experiment and develop methods that enable us to apply it to the study of macromolecules. The model is then applied to study the ice-binding molecule type III thermal hysteresis protein (THP III). A comparison of the hydration of this hydrophobic protein to fasciculin (FAS), a protein of similar size and structure, highlights significant differences in solvent structuring. While our profile of the entire protein surface simply reflects the overall hydrophobicity of each protein, we find that specific subsets of the THP III surface exhibit a strong tendency to enhance the tetrahedral, or ice-like, arrangement of hydrogen bonds within the primary hydration shell