Model Calculations for the Misincorporation of Nucleotides Opposite Five-Membered Exocyclic DNA Adduct: N2,3-Ethenoguanine

Five-membered exocyclic DNA adducts are biologically very significant because of their potential to block DNA replication and transcription. N2,3-Ethenoguanine (N2,3-εG) has been identified in the liver DNA of vinyl chloride-exposed rats as a five-membered DNA adduct. Singer et al. (Carcinogenesis 1987, 8, 745−747) reported that the misincorporation of thymine (T), with two hydrogen bonds to N2,3-εG, represents the mutagenic event. Although the base-pairing specificity and mode of misincorporation have been studied experimentally for the N2,3-ethenoguanine adduct, molecular-level information is not yet clear. In this study, we have considered all four different DNA nucleotides paired with the N2,3-ethenoguanine adduct for model calculations toward the determination of base-pairing specificity. To provide insight into the mutagenic process of DNA damage based on geometric characteristics and electronic properties, the B3LYP and M06 methods were employed for these model calculations. Single-point energy calculations at the MP2/6-311++G** level on the corresponding optimized geometries were also carried out to better estimate the hydrogen-bonding strengths. The polarizable conductor calculation model (CPCM), which accounts for the overall polarizability of the solvent, was also employed. The computed reaction enthalpy values lie in the order εG–G(2) (10.3 kcal/mol) > εG–G(4) (9.6 kcal/mol) > εG–T(4) (9.2 kcal/mol) > εG–G(1) (9.1 kcal/mol) > εG–A(5) (8.2 kcal/mol) > εG–C(2) (7.9 kcal/mol) at the M06 level, which indicates that guanine and thymine are most favorable for mispairing with the N2,3-ethenoguanine adduct.