A . In a second step, the hydroxide ion attacks the scissile phosphate, to reach an associative transition state with a pentavalent phosphate geometry (Figure ). Departure of the leaving group is then associated with only small free energy barriers, as is its reprotonation by a water molecule located in between the two Mg 2+ ions. While our initial mechanistic guess did not impose any reprotonation of the leaving group, a Mg 2+ -bound water molecule spontaneously oriented itself to reprotonate the leaving group during our initial explorations of the reaction free energy landscape.