Oxidation pathways of adenine and guanine in aqueous solution from first principles electrochemistry

The 8-oxo-7,8-dehydropurine tautomers (8-oxoA and 8-oxoG) are mutagenic lesions found in DNA. Two experimental pathways have been proposed for the formation of 8-oxoG: one initiated by deprotonation of the OH˙ radical adduct at the 8-position of guanine (G8OH˙) and the other initiated by a proton-coupled one-electron oxidation of G8OH˙. We here report standard Gibbs energies of the above processes involving proton transfer (PT), electron transfer (ET), and proton-coupled electron transfer (PT–ET) reactions calculated from first principles using DFT (B3LYP) and a continuum solvent model (IEF-PCM). The computed data show that the former pathway is unlikely to occur for A8OH˙ and G8OH˙ in neutral aqueous solution, because of the very low acidity of the hydrogen at the 8-position. In contrast, the latter route involving proton-coupled one-electron oxidations of A8OH˙ and G8OH˙ are exergonic by about 25 kcal mol−1 in aqueous solution. Energetically, adenine and guanine behave similarly toward oxidation to yield 8-oxoA and 8-oxoG. However, the calculated standard Gibbs energetics confirms that the ease of ionization of the native and oxidized forms of nucleobases B to yield the radical cations B˙+ or their deprotonation products B(–H)˙ is 8-oxoG > G > 8-oxoA > A > C > T in aqueous solution. Consequently, 8-oxoG will most readily trap radical cations and neutral radicals in DNA, since it can reduce any nucleobase radical cation B˙+ (via ET) or its deprotonation product B(–H)˙ (via PT–ET) back to the native form of the nucleobase.