A theoretical study towards understanding the origin of DNA oxidation products

Abstract

AbstractReactivity of thymine peroxy radical in DNA and its fate under oxygen‐less condition are studied at DFT B3LYP and M06‐2X functionals together with 6‐31+G(d,p) and aug‐cc‐pVTZ basis sets. The irreversible reaction between OH free radical‐induced C6‐yl and O2 molecule leads to the two main conformers. The spaciously accessible H2′ on the sugar can be abstracted by C6‐peroxy with the estimated barriers of 15.7–21.0 kcal/mol, dependent on various theoretical methods and the conformers. The calculations show that C6‐peroxy has a highly more reactivity towards C (sp3)‐H abstraction reactions than its relative C6‐yl, which is a counter‐intuitive case. Based on the classical Arrhenius rate formula, we find that the vertical electron affinities and proton affinities of the H‐atom acceptors are strongly relevant to electron transfer rate and proton transfer rate, respectively, in the C‐H abstraction reactions. The formed hydroperoxide with the C6‐OaObH2′ constituent can ultrafastly transfer ObH2′ to C2′ radical of the same sugar with a very low barrier (approximately 1.6 kcal/mol) and very strong exothermicity. The results show that the formed hydroperoxide product is too unstable so that it could be quickly transformed into other species and thus is very hard to be experimentally observed. Afterwards, H2′ can be again abstracted by C6‐oxyl radical to result in formation of thymine glycol. The parallel C5‐C6 bond scission reaction leads to formation of the precursor to 5‐hydroxy‐5‐methylhydantion. The two competitive reactions have very low or even negative barriers, dependent on the used functional. Thus, the new radical reaction paths to formation of both thymine glycol and 5‐hydroxy‐5‐methylhydantion are discovered under oxygen‐less condition, which is different from the previously suggested paths under high oxygen concentration surroundings. The influences of the relevant side reactions on formation of the two oxidation damage biomarker molecules are also discussed.