Disentangling the Spatial Resolution of Changes in Solvation Free Energy Using Explicit Solvent Molecular Dynamics Simulations

Understanding solvent-mediated interactions in biomolecular systems at the molecular level is important for the development of predictive models for processes such as protein folding and ligand binding to a host biomolecule. Solvent-mediated interactions can be quantified as changes in the solvation free energy of solvated molecules. Theoretical models of solvent-mediated interactions thus need to include ensemble-averaged solute-solvent interactions. In this thesis, molecular dynamics simulations were coupled with the 3D-2PT method to decompose solvation free energies into spatially resolved local contributions. In the first project, this approach was applied to benzene derivatives to guide the development of efficient and predictive models of solvent-mediated interactions in the context of computational drug design. Specifically, the effects of carboxyl and nitro groups on solvation were studied due to their similar sterical requirements but distinct interactions with water. A system of solvation free energy arithmetics was developed and showed that non-additive contributions to the solvation free energy originate in electrostatic solute-solvent interactions, which are qualitatively reproduced by computationally efficient continuum models. In the second project, a simple model system was used to analyze hydrophilic water-mediated interactions (water-mediated hydrogen bonds), which have been previously suggested to play a key role in protein folding. Using the spatially resolved analysis of solvation free energies, the sites of bridging water molecules were identified as the primary origin of solvent-mediated forces and showed that changes in hydration shell structure can be neglected. In the third project, the analysis of solvation free energy contributions is applied to proteins in inhomogeneous electric fields to explore water-mediated contributions to protein dielectrophoresis. The results provide a potential explanation for negative dielectrophoretic forces on proteins, which have been observed experimentally but cannot be explained with previous theoretical models.