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

Area of Science:

• Computational Chemistry
• Biochemistry
• DNA Damage Mechanisms

Background:

• G-quadruplexes (Gq) are significant secondary structures in B-DNA, acting as therapeutic targets and components in nanodevices.
• Guanine-rich Gq are prone to oxidative damage, initiating DNA damage through radical intermediates formed via proton-transfer reactions.

Purpose of the Study:

• To elucidate the mechanisms of radical intermediate formation in G-quadruplexes (Gq) upon oxidation.
• To computationally investigate the relative stability and pathways of various proton-transfer states in oxidized G-quartets (G4).

Main Methods:

• Density Functional Theory (DFT) calculations, specifically ωB97XD-PCM/6-31++G**, were employed to model the aqueous phase.
• Calculations focused on a single layer of G-quadruplexes (G-quartets, G4), determining relative Gibbs free energies and spin density distributions.

Main Results:

• The study identified G(N2-H)•-(H+N7)G as a key radical intermediate, with an energy only slightly higher (ca. 0.8 kcal/mol) than the initial G•+ state.
• The formation of G(N2-H)•-(H+N7)G is proposed to be critical for the subsequent generation of 8-oxoguanine (8-OG) and G(N1-H)• via tautomerization.

Conclusions:

• The computational findings provide fundamental insights into the early stages of oxidative DNA damage in G-quadruplex structures.
• The identified radical intermediates and pathways offer a mechanistic explanation for the formation of oxidized guanine products like 8-OG.