Density functional investigations on alkali metal (Li, Na, K) catalyzed thymidylyl (3′–5′) thymidine phosphodiester hydrolysis

Alkali metal (Li, Na or K) catalyzed phosphodiester hydrolysis in thymidylyl (3′–5′) thymidine (Tp-OT) has been analyzed employing density functional calculations. Different mechanistic pathways of hydrolysis incorporating one (‘A’ and ‘B’) or two metal ions (‘C’, ‘D’ or ‘E’) are considered. In pathways ‘A’ and ‘B’ the metal ion is bound to different oxygens of diester group. The pathway ‘C’ facilitates formation of six-membered ring wherein OH− interacts with different oxygens of phosphoryl group. On the other hand the energetic associated with pathways which incorporate two metal ions one bound to nucleophile and other interacting with either oxygen on 5′-thymidine (‘D’ pathway) or the alkali metal attached to different oxygens of phosphoryl group in Tp-OT (‘E’ pathway) were also calculated. The reactant, product, intermediate with pentavalent coordinating metal as local minima along with two transition states were identified on the potential energy surface for ‘D’ (in Li and Na) and ‘E’ pathways (for Li, Na, K). Thus, a two-step mechanism comprising of nucleophile attack as initial step followed by departure of 5′-thymidine (the leaving group) has been suggested. Self-consistent reaction field calculations reveal the activation free energies to be: Li (78.8 kJ mol−1) < Na (80.6 kJ mol−1) < K (94.8 kJ mol−1) in the presence water as solvent.