Structural, steric and energetic requirements for induction of base substitutional mutations by methylated guanines and thymines

Abstract

The products of methylation at the N3-, O6- and N7-positions of guanine and at the O2- and O4- positions of thymine are subjected to various possibilities for pairing with DNA bases, using calculations at the semiempirical PM3 SCF-MO level. It is predicted that the presence of the Watson–Crick protons in the modified bases would lead to non-mutagenic base-pairing schemes, while their absence facilitates promutagenic pairing schemes, modified guanines behaving like adenine and modified thymines like cytosine. Some degree of competition with non-mutagenic base-pairing schemes is also anticipated. Only the conformers of the O-methylated bases with the O-methyl group anti to the hydrogen bonding side furnish feasible base-mispairing schemes in the double-helical configuration. The syn conformers do not pair in the double-helical configuration. Correlation of these results with experimental and theoretically predicted Watson–Crick proton acidities for the nucleoside systems leads to the prediction that N3- and O6-methylguanines and O2 and O4-methylthymines would be promutagenic bases at biological pH, while N1-methylguanine would behave without miscoding properties. These predictions are largely confirmed by the reported experimental template properties of these modified DNA bases and are also corroborated by NMR, UV and crystallography studies on some of the modified bases considered here.