Free Energy Calculations in Action: Theory, Applications and Challenges of Solvation Free Energies

Author(s): Duarte Ramos Matos, Guilherme | Advisor(s): Mobley, David L | Abstract: Free energy calculations play an essential role in the study of physical transformations and chemical reactions. Within the universe of free energy calculation applications, solvation free energies (Gsolv) have a leading role: they are easy to calculate and have a broad scope of applications, from the study distribution coefficients between two phases to solubility prediction. This dissertation discusses some of the uses of Gsolv as a tool for method development, as a way to calculate infinite dilution activity coefficients, and as a part of an effort to predict solubilities of molecular solids.In chapters 2 and 3, I discuss the general features of solvation free energy calculations and their applications. We also introduced an update of FreeSolv, a hydration free energy database, and the use of infinite activity coefficient calculations (IDACs) as assisting tools (or potentially substitutes) of hydration free energies in force field parameterization and method development. Chapter 4 discusses the reproducibility of relative alchemical free energies (RAFE) across different software (AMBER, GROMACS, SOMD, CHARMM). We demonstrated that Ghyd can be reproduced to within about +0.2 kcal /mol and we highlighted the differences and particularities of each code. I was responsible for running the simulations and analyzing the results of the GROMACS code. Chapter 5 discusses an application of free energy calculations to the prediction of solubilities. I attempted to predict the solubility of acetylsalicylic acid (ASA) by calculating the absolute chemical potentials of the most stable polymorph of ASA and of solutions of different concentrations. Despite not finding a result that agreed with experimental error, I outlined the strengths and weaknesses of the method used and suggested improvements for future attempts.