DFT calculations on the electrophilic reaction with water of the guanine and adenine radical cations. A model for the situation in DNAElectronic Supplementary Information available. See http://www.rsc.org/suppdata/cp/b1/b109204a/

Using density functional theory, the H2O (modeled by OH−) addition on the C8-site of the guanine and adenine radical cations (Gua˙+/Ade˙+) is calculated to be exothermic by −75.3 and −77.7 kcal mol−1, respectively. In contrast, in the absence of the N1 proton on Gua˙+, i.e., in the case of the neutral radical (Gua(–H)˙) the H2O addition is +29.4 kcal mol−1endothermic. Similarly, in the case of the neutral adenine radical (Ade(–H)˙), the N6-deprotonated radical cation, the H2O addition is endothermic by +43.7 kcal mol−1. Related to these observations is the fact that with the radical cations, Gua˙+and Ade˙+, the positive charge density on the C8-carbon is higher than with the deprotonated forms. This means that nucleophilic attack is likely to have a lower activation energy in the case of the former than the latter. The protonated radical, Gua˙+, simulates the situation in double-stranded (ds) DNA where the transfer of the N1 proton to solvent molecules is inhibited due to its base pairing with cytosine. In contrast, in single-stranded DNA and in RNA, Gua˙+ is expected to quickly lose its N1 proton to the water phase. In comparison, with Ade˙+ in ds DNA the exocyclic N6-atom is in contact with water molecules in the major groove of the DNA double helix and thus should be able to rapidly lose a proton to a water molecule, even when it is paired with thymine. This concept provides an explanation for the experimental observation of 7,8-dihydro-8-oxoguanine (8-OGua) formation only in ds DNA and negligible formation of 7,8-dihydro-8-oxoadenine (8-OAde) in any other form of DNA.