The Hydrolysis of Amides and the Proficiency of Amidohydrolases. The Burden Borne by k_w

The hydrolysis of small amides has garnered major attention due to its relevance to peptide hydrolysis, one of the most fundamental reactions of biology. Both experimental and theoretical research efforts have studied the reaction in different media, and a consensus has been reached regarding the specific acid- and base-catalyzed reaction pathways. Nevertheless, for the water reaction, large discrepancies between theoretical and experimental results are found in the literature. Herein, we report the results of theoretical calculations of formamide and urea hydrolysis at different pH values. Model systems have been built clustering one and two water molecules with the reactive amide. A careful analysis of the reaction pathways at different temperatures has allowed us to accurately reproduce available experimental data and to separate the water reactions from their acid and base counterparts. The relevance of the results in providing an accurate definition of the proficiency of amidohydrolases is discussed.