Role of Deprotonation Free Energies in pKa Prediction and Molecule Ranking

A computationally efficient classical molecular simulation technique is derived for ranking the pKa values of a set of chemically similar congeneric molecules in an implicit solvent model of water. This uses the deprotonation free energy of the titratable group in the gas and aqueous phases obtained by thermodynamic integration (TI). For a series of alcohols and acids a strong linear correlation is demonstrated between the experimental pKa and the deprotonation free energy difference in the gas and liquid phases. These calculations also show that classical TI is more efficient than slow-growth TI in calculating deprotonation free energies for the series of molecules considered herein.