A general acid-general base reaction mechanism for human brain aspartoacylase: A QM/MM study

► QM/MM studies the reaction mechanism of human brain aspartoacylase. ► The reaction proceeds via a promoted-water pathway, not an anhydride mechanism. ► The reaction barrier is in excellent agreement with experimental observation. ► The Zn2+ activates the water nucleophile and stabilizes the transition state. ► The Arg63 serves as an oxyanion hole stabilizing the transition state.