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. rst 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.