Calculation of electrostatic interaction and solvation free energies in biomolecular systems

Biological structure, function and kinetics are fundamentally based on a balance of interactions between solute and solvent molecules. This fact poses a significant challenge for theoretical treatments of biological processes, in that both solute and solvent interactions must be accurately quantitated in order to gain insights into the driving forces involved. The goal of this thesis is to accurately determine the magnitudes of solute and solvent interactions in biomolecular systems, using a theoretical approach that relies on continuum solvent models. The continuum method computes electrostatic interactions by solving the Poisson-Boltzmann (PB) Equation for charges in a polarizable cavity embedded in a dielectric medium. Nonpolar interactions are added by applying the concept of interfacial tension at a molecular level. The continuum solvent method is applied to several simple systems of biological importance, namely small molecules representing the amino acids and an alpha helical peptide, in order to investigate and develop the accuracy of calculations, as well as estimate the importance of both solute and solvent interaction energies. Subsequently, the treatment is used in minimizations of protein structures in solution, where the balance between intra-solute and solute-solvent interactions is of key consequence. The results provide strong evidence that the continuum solvent approach can provide a reliable estimate of solvation and solute-solute forces and energies. Solvation effects, solute polarizability and long-range interactions between charged amino acids are found to be important factors to biological structure and stability. Helix dipole effects are localized to the helix termini. This thesis extends the accuracy of the PB dielectric and nonpolar interfacial tension continuum solvent methods, so that reliable estimates of solute and solvent interactions in small molecules as well as proteins can be obtained. The results provide a deeper understanding of the contributions from solvation, solute polarizability, charge-charge interactions, and helix dipole effects to molecular energetics and stabilities. The work presented here opens the way toward more accurate calculations of the effects of surrounding protein and solvent on protein structural stability, dynamics, and function