A procedure to understanding the C-G to A-T transversion. SMD simulations from guanine oxidation pathways assisted by one H2O2 molecule in the C-G basis pair

Abstract

The C-G to A-T transversion in the gas and aqueous phases was studied through steered molecular dynamic (SMD) simulations. The mechanism considered involved the guanine oxidation to 8-oxoguanine (G*) assisted by one H2O2 molecule from two pathways, the C-G base pair dissociation, and the A-T and G*-A bases pair associations. The guanine oxidation, with energies much higher than those of the associations between base pairs, was responsible for the spontaneity of the transversion. The a-pathway, through the 8-OH-guanine stable intermediate, was the most exergonic (ΔGa = −95.46 kcal·mol−1) and fast (ka = 1.21 · 10−12 s−1). The b-pathway, through an 8-OOH-guanine unstable intermediate, was less exergonic (ΔGb = −62.05 kcal·mol−1) and slow (kb = 1.95 · 10−24 s−1). The presence of the aqueous solvent modifies the kinetics and thermodynamics of the transversion, keeping the greatest spontaneity by the a-pathway (ΔGa = −84.00 kcal·mol−1; ΔGb = −72.38 kcal·mol−1). These results agree with other ab initio studies although they differ in some units, due to the difference methods and mechanisms use. The long lifetimes of the G* molecule and the A-T pair formed during this transversion show that these species could participate in genetic mutations, especially when the oxidation process starts with the attack of OH radicals on the C8 and H8 atoms of the guanine base. Molecular structures of the species involved in the mechanisms were analysed along the reaction path, which allowed us to obtain the energy profile over time and to calculate kinetic and thermodynamic properties at every step of the simulation.