On the evolution of one-electron-oxidized deoxyguanosine in damaged DNA under physiological conditions: a DFT and ONIOM study on proton transfer and equilibrium

Abstract

Different deprotonation paths of the radical cation formed by one-electron oxidation of 2'-deoxyguanosine (2dG) sites in DNA have been studied using Density Functional Theory (M05-2X/6-31+G(d,p)) and ONIOM methodology (M05-2X/6-31+G(d,p):PM6) in conjunction with the SMD model to include the solvent effects. Models of increased complexity have been used ranging from the isolated nucleoside to a three unit double-stranded oligomer including the sugar units, the base pairing with cytidine, and the phosphate linkage. The reported results correspond to aqueous solution, at room temperature, and pH = 7.4. Under such conditions it was found that the proton transfer (PT) within the base pair is a minor path compared to the PT between the base pair and the surrounding water. It was also found that the deprotonation of ground-state 2dG˙(+) sites mainly yields C centered radicals in the sugar unit, with the largest populations corresponding to C4'˙ and C5'˙, followed by C3'˙. The different aspects of the presented theoretical study have been validated with experimental results.

Melatonin and its metabolites as chemical agents capable of directly repairing oxidized DNA

“…On the other hand, the low‐level layer was computed using PM6, which is among the most accurate semiempirical methods, especially for energies and geometries of systems presenting hydrogen bonding . This model has been successfully used before …”

“…The first step is assumed to consist of single electron transfer (SET) from guanosine sites, which it is the most easily oxidized of the nucleic acid bases, with a reduction potential of 1.29 V vs NHE . The radical cation generated in the first oxidative stage readily deprotonates, under physiological conditions, yielding C‐centered radicals mainly located in the deoxyribose unit . These radicals are also produced by direct hydrogen atom transfer (HAT) from the sugar sites to ˙OH .…”

Computational strategies for predicting free radical scavengers' protection against oxidative stress: Where are we and what might follow?

“…Among them, the most important is expected to be deprotonation, considering the rather low p K a value of the radical cation (3.9) . Carbon centered radicals, in the sugar unit, are predicted to be the main deprotonation products at room, or body, temperatures . They are particularly dangerous because of their involvement in DNA strand breaks .…”

Thiophenols, Promising Scavengers of Peroxyl Radicals: Mechanisms and kinetics

“…ROS and free radicals are naturally produced in healthy organisms at low concentrations as a consequence of normal metabolism and, in this case, they have beneficial functions . However, when their concentrations increase too much, they may represent a major health problem .…”