Hydroxyl Radical Reaction with the Guanine-Cytosine Base Pair: A Density Functional Theory Study

Abstract

To address problems such as aging, mutation, and cancer, it is of great importance to understand the damage mechanism of DNA induced by hydroxyl radical. In this study, the abstraction reaction mechanism of hydroxyl radical with guanine-cytosine (GC) base pair in aqueous phase under the polarized continuum model (PCM) has been explored by using density functional theory (DFT). The results indicated that all the abstraction reactions in GC base pair were thermodynamically exothermic, and the stability of dehydrogenation radicals decreased in the order of (H2b-GC) • >(GC-H4b) • >(GC-H6) • >(GC-H5) •~(H8-GC) •. The reaction energy of H2b abstraction pathway was the lowest among all investigated pathways, thus indicating that the reaction conversion of (H2b-GC) • was the highest. In the five hydrogen abstraction pathways, the local energy barriers with respect to the corresponding reactant complexes increased in the following order: H2b<H4b<H5<H6<H8, thereby suggesting that the H2b abstraction pathway was the most rapid. Thus, H2b abstraction process was the most likely favorable reaction pathway. Another compatible pathway would be the H4b abstraction, followed by H6 and H5 abstraction pathways in thermodynamics and in kinetics. H8 abstraction process was the least favorable pathway, as consistent with the formation of hydroxylation adduct observed experimentally rather than the hydrogen abstraction radical.

DFT Study of the Hydroxyl Radical Addition to 2′-Deoxyguanosine and the Guanine Base in Four Double-Stranded B-Form Dimers

“…Many computational studies of the guanine (or G.C pair)···HO • interaction have been reported. − However, a theoretical comparison of three HO • additions to dR-Gua (to C(4), C(5), and C(8)) has not been made so far. Also, it has not been examined whether and how three OH adducts undergo the ring cleavage.…”