Computation of phosphodiester hydrolysis in different models with one or two
metal ions, representing typical active site architectures of nucleases,
reveals an associative mechanism to be favorable in all of the cases studied
in this work. Direct attack of the nucleophilic water molecule with proton
transfer to the phosphate group is facilitated by an extra positive charge as
provided by a metal ion located at the attack site or a positively charged
histidine residue, whereas no such contribution can be observed on leaving
group departure. A major catalytic effect is found by proton transfer from the
nucleophilic water molecule to a histidine–aspartate cluster. Attack of the
thus generated hydroxide ion on the phosphate group is just sufficiently
stabilized by the metal ions to allow subsequent P–O bond dissociation