The impact of protonation and deprotonation of 3-methyl-2′-deoxyadenosine on N-glycosidic bond cleavage

Abstract

The enzyme–substrate contacts that are believed to be involved in depurination by proton transfer have been modelled by protonation and deprotonation of 3-methyl-2′-deoxyadenosine (3-MDA) using quantum mechanical calculations in the gas-phase and solution media. The change in the charge distribution on the sugar ring and nucleobase that is introduced by the protonation and deprotonation strongly affects the N-glycosidic bond length. The unimolecular cleavage and hydrolysis of the N-glycosidic bond, involving D_N*A_N and A_ND_N pathways, have been considered at several levels of theory. The trend in the energy barriers is A_ND_N > cleavage > D_N*A_N. All probable proton transfer reactions resulting from enzyme–substrate contacts do not facilitate the N-glycosidic bond cleavage of 3-MDA. The deprotonation of 3-MDA that may result from the interaction between H6 and enzyme do not facilitate bond cleavage. The protonation at N7 induces more positive charge on the sugar ring and further facilitates the depurination relative to the protonation at N1. The changes in the charges calculated on the ribose and nucleobase are in good relationship with the C1′–C2′, C1′–O4′, and N-glycosidic bond lengths along the cleavage. The change in energy barrier ΔE of glycosidic bond cleavage from the gas-phase to solution media strongly depends on the charge of the species.