It has been proposed that BACE1 and aspartic proteases catalyze peptide bond hydrolysis through an acid-base catalysis mechanism mediated by Wat1 and the Asp pair as follows. (i) After substrate binding, the free Asp pair activates Wat1 by forming a hydrogen bond with it. (ii) Next, the activated Wat1, it has been proposed, nucleophilically attacks the scissile-bond carbonyl. The resulting geminal diol intermediate is stabilized by hydrogen bonds with the carboxyl group of Asp.