Ab Initio Evaluation of the Free Energy Surfaces for the General Base/Acid Catalyzed Thiolysis of Formamide and the Hydrolysis of Methyl Thiolformate: A Reference Solution Reaction for Studies of Cysteine Proteases

Abstract

Although the catalytic reaction of cysteine proteases is a process of major importance, we do not have a quantitative understanding of the relevant energetics. The present work takes a crucial step in this direction and determines the free energy surface for the corresponding reference solution reaction. The calculations involve the evaluation of the potentials of the mean force for ammonia-, histidine, and water-assisted reactions of thiomethanol with formamide in aqueous solution, as well as for the hydrolysis of the resulting thiolester. These calculations were carried out using the quantum mechanical B3LYP/AUG-cc-pVDZ//HF/6-31G* method and the Langevin dipoles solvation model. The calculations involve self-consistent evaluation of the solute charges in solution as well as mapping the solution free energy surface (rather than the gas-phase surface). The amide thiolysis (acylation step) was found to have a stepwise character with equal activation barriers of 24 kcal/mol for histidine-assisted nucleophil...