Nucleophilic substitution at di- and triphosphates: leaving group ability of phosphate versus diphosphate

Adenosine triphosphate (ATP) is the universal energy carrier in biochemical processes. Herein, we aim for a better understanding of the origin of the high-energy content of the triphosphate moiety involved, the influence of various physicochemical factors thereon, and implication for the actual SN2@P-induced hydrolysis, which drives uphill biochemical processes, such as, DNA replication. To this end, we have investigated the SN2@P-induced hydrolysis of triphosphate (PPP) versus that of diphosphate (PP) using density functional theory (DFT) at COSMO(H2O)-ZORA-OLYP/TZ2P. We find that SN2@P-induced hydrolysis of PPP is favored over that of PP, both kinetically and thermodynamically. The energetic advantage of PPP over PP is slightly diminished by the coordination of Mg2+ counterions. Our activation strain and energy decomposition analyses reveal that the activation barrier for PPP hydrolysis is lower compared to that for PP due to a weaker Pα–O leaving group bond.