To elucidate the catalytic power of enzymes it is crucial to have clear information about the corresponding reference reactions in solution. This is needed since catalysis is defined by comparing enzymatic reactions to the relevant uncatalyzed reactions. Unfortunately, the energetics of the reference reactions of many important classes of enzymatic reactions have not been fully determined by experimental studies. In many cases it is hard to determine whether the given reaction involves a stepwise or a concerted mechanism, It is also hard to estimate the activation barrier for steps which are not rate determining. Fortunately, it is possible now to use computational approaches to augment the available experiments and to elucidate the shape of free energy surfaces of various reference reactions. Here we present a systematic study of the reference solution reaction for studies of serine proteases, i.e., the base-catalyzed and general base/acid catalyzed methanolysis of formamide, The present work is based on the use of combined ab initio/Langevin dipoles calculations and on a careful comparison to available experiments. The applied ab initio methodologies involve nonlocal density functional (B3LYP/AUG-cc-pVDZ) calculations and G2 theory. The construction of the relevant free energy surfaces involves partial geometry optimizations for the ammonia-catalyzed methanolysis of formamide, Subsequently, energy corrections based on the appropriate experimental pK(a), values are applied to construct interpolated free energy surfaces for the water-and histidine-catalyzed reactions. Crucial points on the free energy surface for the water catalyzed reaction are also evaluated independently. We start by exploring the first step of the alcoholysis reaction, which involves a proton transfer from ROH to a base, a nucleophilic attack of RO- on the amide, and a formation of a tetrahedral intermediate anion (TI), The interpolated free energy surface for the water-assisted alcoholysis involves a least energy path where the proton transfer is concerted with the nucleophilic attack. The corresponding activation barrier is similar to 32 kcal/mol, The independently calculated surface for this reaction involves an activation barrier of similar to 34 kcal/mol. These results are in a good agreement with the corresponding experimentally observed barrier (30-32 kcal/mol), The interpolated free energy surface for the histidine-catalyzed reaction involves a stepwise path, with a shallow surface that can also allow for a concerted path. This free energy surface is quite different than the fully concerted surface obtained in previous theoretical studies. The calculated activation barrier for the hisitidine-catalyzed reaction is around 26 kcal/mol. To examine the next step of the reaction we evaluated the basicities of the O and N atoms of the TI. These values were found to be 14 and 8 pK(a) units, respectively. The calculated pK(a) of the N atom indicates that the leaving group is protonated prior to the cleavage of the CN bond. The activation free energy for the CN bond cleavage is predicted to be 22 kcal/mol at 298 K. This barrier is independent of the nature of the general base. It is concluded that the nucleophilic attack is the rate-determining step for the acylation reaction studied. After this step, the reaction surface is rather flat, with only small barriers separating anionic and N-protonated TI from the product valley, The TI may become stabilized by the formation of the O-protonated form. The presented potential surface for the reaction with histidine as a base should provide a useful way for validating quantum mechanical studies of serine proteases, This surface should also allow the calibration of semiempirical approaches that can be used in studies of these enzymes.