Multifaceted Computational Analysis of O6-Methylguanine and O6-Methylthioguanine Nucleobase Complexes

Improper DNA methylation yields O6-methylguanine, which induces GC-AT mutations if left unchecked by O6-methylguanine DNA methyltransferase (MGMT). Previous ab initio studies have computed the interaction energy of O6-methylguanine with cytosine and thymine, but this study probes deeper by investigating the noncovalent interactions through various forms of energy decomposition analysis. The same methods are then applied to the sulfur analog of O6-methylguanine, S6-methylthioguanine, which is likewise highly mutagenic but has received considerably less computational treatment. Interaction energies computed at the ωB97X-D3/aug-cc-pVTZ and SAPT2+/aug-cc-pVDZ levels of theory revealed that O6-methylguanine and S6-methylthioguanine form substantially weaker complexes than the unmethylated G:C and TG:C pairs yet may continue to prefer binding to cytosine over thymine. NCI and NBO analyses demonstrated that the O6-methylguanine and S6-methylthioguanine complexes with cytosine or thymine are driven primarily by two hydrogen bonds, which are noticeably weaker than the average hydrogen bond observed among the canonical base pairs. The molecular electrostatic potential (MEP) of these nucleobases likewise predicted that the exocyclic amine on O6-methylguanine and S6-methylthioguanine is less electrophilic than the H-bond donors on guanine and thioguanine. In direct comparison to O6-methylguanine, the S6-methylthioguanine complexes are qualitatively similar but exhibit weaker hydrogen bonding and greater dispersion forces.