Deprotonation of 8-Oxo-7,8-dihydroadenine Radical Cation in Free and Encumbered Context: A Theoretical Study

Due to the lower oxidation potential than natural nucleic acid bases, one-electron oxidation of DNA is usually funneled into the direction of intermediates for oxidized DNA damage like 8-oxo-7,8-dihydroadenine (8-oxoA) leading to a radical cation, which may undergo facile deprotonation. However, compared to the sophisticated studies devoted to natural bases, much less is known about the radical cation degradation behavior of an oxidized DNA base. Inspired by this, a comprehensive theoretical investigation is performed to illuminate the deprotonation of 8-oxoA radical cation (8-oxoA^•+) in both free and encumbered context by calculating the pK _a value and mapping the energy profiles. The calculative pK _a values of active protons in free 8-oxoA^•+ follow the order: N7-H < N9-H < N6-H1< N6-H2, suggesting the preference of proton departure in free 8-oxoA^•+. To further illustrate the preferred site and mechanism for 8-oxoA^•+ deprotonation, energy profiles are constructed to distinguish the possibility from that of all active protons in both contexts. The results show distinctly that 8-oxoA^•+ mainly suffers from the loss of proton from N9 due to the lowest energy barrier but deprotonates N7-H in real DNA as the connection of N9 and ribose. The energy barriers for the deprotonation of N7-H from 8-oxoA^•+ in free and encumbered contexts are 1.5 and 1.3 kcal/mol, respectively, indicating a fast deprotonation reaction. It is more interestingly that the N9-H proton transfer (PT, toward N3) to adjacent water follows a stepwise fashion rather than a one-step approach as previously reported. Furthermore, the PT behavior of free N9-H toward O8 is dramatically influenced by base pairing T, where it is localized at neighboring water without further PT to adjacent water in free 8-oxoA^•+ but migrated directly to adjacent water in the 8-oxoA^•+:T base pair. And the deprotonation of N6-H2 in 8-oxoA^•+:T is disturbed as the PT to O4 of the pairing T base is inhibited. It is warmly anticipated that these results could provide an in-depth perspective to understand the important role of 8-oxoA in mutation.