Proton-Transfer Reactions in One-Electron-Oxidized G-Quadruplexes: A Density Functional Theory Study

Recently, G-quadruplexes (Gq) formed in B-DNA as secondary structures are found to be important therapeutic targets and material for developing nanodevices. Gq are guanine-rich and thus susceptible to oxidative damage by producing short-lived intermediate radicals via proton-transfer reactions. Under-standing the mechanisms of radical formation in Gq is of fundamental interest to understand the early stages of DNA damage. Herein, we used density functional theory including aqueous phase (omega B97XD-PCM/6-31++G**) and considered single layer of Gq [G-quartets (G4): association of four guanines in a cyclic Hoogsteen hydrogen-bonded arrangement (Scheme 1)] to unravel the mechanisms of formation of intermediates by calculating the relative Gibbs free energies and spin density distributions of one-electron-oxidized G4 and its various proton-transfer states: G(center dot+), G(N-1-H)(center dot), G(N-2-H ')(center dot), G(N-2-H '')(center dot), G(N-1-H)(center dot)-(H+O6)G, and G(N-2-H)center dot-(H+N7)G. The present calculation predicts the formation of G(N-2-H)(center dot)-(H+N7)G, which is only ca. 0.8 kcal/mol higher in energy than the initially formed G(center dot+). The formation of G(N-2-H)(center dot)-(H+N7)G plays a key role in explaining the formation of 8-OG along with G(N-1-H)(center dot) formation via tautomerization from G(N-2-H)(center dot), as proposed recently.