Deprotonation of\n8‑Oxo-7,8-dihydroadenine Radical\nCation in Free and Encumbered Context: A Theoretical Study

Due to the lower oxidation potential than natural nucleic\nacid\nbases, one-electron oxidation of DNA is usually funneled into the\ndirection of intermediates for oxidized DNA damage like 8-oxo-7,8-dihydroadenine\n(8-oxoA) leading to a radical cation, which may undergo facile deprotonation.\nHowever, compared to the sophisticated studies devoted to natural\nbases, much less is known about the radical cation degradation behavior\nof an oxidized DNA base. Inspired by this, a comprehensive theoretical\ninvestigation is performed to illuminate the deprotonation of 8-oxoA\nradical cation (8-oxoA<sup>•+</sup>) in both free and encumbered\ncontext by calculating the p<i>K</i><sub>a</sub> value and\nmapping the energy profiles. The calculative p<i>K</i><sub>a</sub> values of active protons in free 8-oxoA<sup>•+</sup> follow the order: N7–H < N9–H < N6–H1<\nN6–H2, suggesting the preference of proton departure in free\n8-oxoA<sup>•+</sup>. To further illustrate the preferred site\nand mechanism for 8-oxoA<sup>•+</sup> deprotonation, energy\nprofiles are constructed to distinguish the possibility from that\nof all active protons in both contexts. The results show distinctly\nthat 8-oxoA<sup>•+</sup> mainly suffers from the loss of proton\nfrom N9 due to the lowest energy barrier but deprotonates N7–H\nin real DNA as the connection of N9 and ribose. The energy barriers\nfor the deprotonation of N7–H from 8-oxoA<sup>•+</sup> in free and encumbered contexts are 1.5 and 1.3 kcal/mol, respectively,\nindicating a fast deprotonation reaction. It is more interestingly\nthat the N9–H proton transfer (PT, toward N3) to adjacent water\nfollows a stepwise fashion rather than a one-step approach as previously\nreported. Furthermore, the PT behavior of free N9–H toward\nO8 is dramatically influenced by base pairing T, where it is localized\nat neighboring water without further PT to adjacent water in free\n8-oxoA<sup>•+</sup> but migrated directly to adjacent water\nin the 8-oxoA<sup>•+</sup>:T base pair. And the deprotonation\nof N6–H2 in 8-oxoA<sup>•+</sup>:T is disturbed as the\nPT to O4 of the pairing T base is inhibited. It is warmly anticipated\nthat these results could provide an in-depth perspective to understand\nthe important role of 8-oxoA in mutation.