Comparison of inline and non-inline associative and dissociative reaction pathways for model reactions of phosphate monoester hydrolysis

Abstract

The energies, geometries and transition state orders for several different potential phosphate ester group hydrolysis mechanisms are determined at different levels of phosphate group and nucleophile prnotonation to define factors which might favour one phosphoryl group transfer mechanism over another. With respect to the phosphate ester group, protonation is considered as a generic model for phosphate anion charge neutralisation by, for example, alkylation or metal ion chelation. The results indicate that the protonation state of either the phosphate group and/or the nucleophile can produce dramatic changes in the relative energies of intermediates and transition states for any particular hydrolytic mechanism and that the magnitude of the changes can be sufficiently large to cause a change in favoured mechanism. For example, the results of the calculations predict that the favoured mechanism should change from a dissociative one at low levels of phosphate group protonation, to an associative one at higher levels of phosphate group protonation. Furthermore, the results indicate that under conditions in which a highly stable pentacoordinate intermediate is formed, the favoured reaction pathway involves a non-inline displacement of the leaving group by the nucleophile rather than an inline displacement. The relevance of these findings to understanding enzyme-catalysed phosphoryl group transfer is discussed.