Molecular criteria for mutagenesis by DNA methylation: Some computational elucidations

Highlights: • Estimates of Watson-Crick proton abstraction energies differentiate the non-mutagenic N7-methylguanine from the promutagenic O6-methylguanine and O4-methylthymine in good accord with trends shown by experimental pKa values. • Conformational analysis of the O6-methylguanine and O4-methylthymine systems indicate that a certain barrier has to be crossed for them to attain the anti conformer suitable for Watson-Crick type base pairing. • The cationic non-miscoding N7-MeGua⁺⋯Cyt pair is expected to predominate at biological pH due to the pKa value of 7.2 for N7-methylguanine. - Abstract: Alkylating agents and N-nitroso compounds are well-known mutagens and carcinogens which act by alkylating DNA at the nucleobase moieties. Criteria for mutagenicity through DNA alkylation include (a) absence of the Watson-Crick (N1-guanine and N3-thymine) protons, (b) rotation of the alkyl group away from the H-bonding zone, (c) configuration of the alkylated base pair close to the Watson-Crick type. This computational study brings together these three molecular criteria for the first time. Three methylated DNA bases—N7-methylguanine, O6-methylguanine and O4-methylthymine—are studied using computational chemical methods. Watson-Crick proton loss is predicted more feasible for the mutagenic O6-methylguanine and O4-methylthymine than for the non-mutagenic N7-methylguanine in agreement with the observed trend for pKa values. Attainment of a conformer conducive to mutagenesis is more feasible for O6-methylguanine than for O4-methylthymine, though the latter is more mutagenic. These methylated bases yield 9 H-bonded pairs with normal DNA bases. At biological pH, O6-methylguanine and O4-methylthymine would yield stable mutagenic pairs having Watson-Crick type configuration by H-bonded pairing with thymine and guanine respectively, while N7-methylguanine would yield a non-mutagenic pair with cytosine. The three criteria thus well differentiate the non-mutagenic N7-methylguanine from the mutagenic O6-methylguanine and O4-methylthymine in good accord with experimental observations.