Singlet Oxygen Attack on Guanine: Reactivity and Structural Signature within the B-DNA Helix

摘要

Oxidatively generated DNA lesions are numerous and versatile, and have been the subject of intensive research since the discovery of 8-oxoguanine in 1984. Even for this prototypical lesion, the precise mechanism of formation remains elusive due to the inherent difficulties in characterizing high-energy intermediates. We have probed the stability of the guanine endoperoxide in B-DNA as a key intermediate and determined a unique activation free energy of around 6kcalmol(-1) for the formation of the first C-O covalent bond upon the attack of singlet molecular oxygen (O-1(2)) on the central guanine of a solvated 13base-pair poly(dG-dC), described by means of quantum mechanics/molecular mechanics (QM/MM) simulations. The B-helix remains stable upon oxidation in spite of the bulky character of the guanine endoperoxide. Our modeling study has revealed the nature of the versatile O-1(2) attack in terms of free energy and shows a sensitivity to electrostatics and solvation as it involves a charge-separated intermediate.