First principles calculations of the pKa values and tautomers of isoguanine and xanthine.

The accurate replication of DNA requires the formation of complementary hydrogen bonds between a template base and the base moiety of an incoming deoxynucleotide-5'-triphosphate. Recent structural studies suggest that some DNA polymerases contribute additional constraints by interrogating the minor groove face of the incoming and template bases. Therefore, the hydrogen bond-donating or -accepting properties of the base pairing as well as minor groove faces of the bases could be important determinants of correct base selection. In this paper, we investigate two purines that could arise by endogenous damage of the normal DNA bases: isoguanine (which can be generated by the oxidation of adenine) and xanthine (which can be generated by the deamination of guanine). In both cases, the potential exists for the placement of a proton in the N3 position, converting the N3 position from a hydrogen bond acceptor to a donor. In this paper, we use first principles quantum mechanical methods (density functional theory using the B3LYP functional and the 6-31G++Gbasis set) to predict the ionization and tautomeric equilibria of both isoguanine and xanthine in the gas phase and aqueous solution. For isoguanine, we find that the N1H and N3H neutral tautomeric forms are about equally populated in aqueous solution, while the enol tauotomers are predominant in the gas phase. In contrast, we find that xanthine displays essentially no tautomeric shifts in aqueous solution but is nearly equally populated by both an anionic and a neutral form at physiological pH. To obtain these results, we carried out an extensive examination of the tautomeric and ionic configurations for both xanthine and isoguanine in solution and in the gas phase. The potential hydrogen-bonding characteristics of these damaged purines may be used to test predictions of the important components of base selection by different DNA polymerases during DNA replication.