Theoretical insights into the reaction mechanism of hydroxyl radicals and guanine in G-quadruplex DNA.

A DFT investigation was performed to illuminate the obscure mechanism of hydroxyl radical (OH˙) and guanine in G-quadruplex by mapping the energy profiles for both addition and hydrogen abstraction reactions. Results revealed that in G-quadruplex, the electrophilic attack of OH˙ to C8 (G) leading to 8-oxoG is the most energetically favorable course, where direct hydrogen abstraction from N2 of G to furnish neutral radicals could compete with that. Although the addition of OH˙ to C4 and C5 positions could provide stable OH-adducts, the subsequent dehydration of C4-OH adduct and hydrogen transfer of C5-OH adduct, which is a prerequisite for neutral radical formation, is rate-limited due to the high barrier manifesting the inaccessibility for these courses. Intriguingly, the identity of the decisive neutral radical was confirmed to be G(N2-H)˙ rather than the familiar G(N1-H)˙, where the hydrogen bond plays significant roles by blocking tautomerizations.