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 nucleophilic attack on amide, and the elimination of NH3 from the resulting tetrahedral intermediate. This mechanism is quite different than the mechanism suggested by previous gasphase theoretical studies. The subsequent hydrolysis of methyl thiolformate (deacylation step) also has stepwise character, with H2O attack in the histidine-assisted reaction characterized by a barrier of 26 kcal/mol. The anionic tetrahedral intermediate formed by this attack decomposes into formic acid and thiolate anion with the activation free energy of 25 kcal/mol. Our calculations lead to the conclusion that the active sites of cysteine proteases must provide substantial stabilization to four different transition state structures.