Repair of O6-methylguanine to guanine by cysteine in the absence and presence of histidine and by cysteine thiolate anion: a quantum chemical study

O6-methylguanine (O6mG) is known to be a potential mutagenic modification of guanine as it mispairs with thymine in DNA and causes GC to AT transversion mutation. It is experimentally known that O6mG can be repaired to guanine by the protein O6-alkylguanine-DNA alkyltransferase (AGT), a cysteine residue being the main active site. In the present work, the mechanisms of repair of cis-O6-methylguanine (O6mG) to guanine due to its reaction with cysteine in the absence and presence of histidine and with cysteine thiolate anion were investigated theoretically using the B3LYP hybrid functional of density functional theory and the second order Møller–Plesset perturbation (MP2) theory. Reactant, intermediate and product complexes as well as transition states involved in these reactions were fully optimized at the B3LYP/6-31+G* level of theory in the gas phase. The solvent effect of water was treated using the polarizable continuum model (PCM). Single point energy calculations were performed at the B3LYP/AUG-cc-pVDZ and MP2/6-31+G* levels of theory in the gas phase and aqueous media. It is found that cysteine alone can repair the cis-O6mG to guanine, but the involvement of histidine along with cysteine lowers down the barrier energy significantly. However, when cysteine thiolate anion is used in place of cysteine, the barrier energy is strongly reduced. These results broadly support the suggestions based on experimental studies.