A quantum chemical study of repair of O6-methylguanine to guanine by tyrosine: Evaluation of the winged helix-turn-helix model

The winged helix-turn-helix model for the repair of O6-MeG to guanine involving the reaction of O6-MeG with a tyrosine residue of the protein O6-alkylguanine-DNA alkyltransferase (AGT) was examined by studying the reaction mechanism and barrier energies. Molecular geometries of the species and complexes involved in the reaction, i.e. the reactant, intermediate and product complexes as well as transition states, were optimized employing density functional theory in gas phase. It was followed by single point energy calculations using density functional theory along with a higher basis set and second order M phi ller-Plesset perturbation theory (MP2) along with two different basis sets in gas phase and aqueous media. For the solvation calculations in aqueous media, the integral equation formalism of the polarizable continuum model (IEF-PCM) was employed. Vibrational frequency analysis was performed for each optimized structure and genuineness of transition states was ensured by visualizing the vibrational modes. It is found that tyrosine can repair O6-MeG to guanine by a two-step reaction. The present results have been compared with those obtained considering the helix-turn-helix model where the repair reaction primarily involves cysteine and occurs in a single-step. It is concluded that the repair through tyrosine envisaged in the winged helix-turn-helix model would be less efficient than that through cysteine envisaged in the helix-turn-helix model.