Mechanisms for the Decomposition of Hydroxyl-Radical-Induced Cytosine Hydroperoxides: A Computational Study

Abstract

Hydroxyl-radical-induced damage to cytosine leads to a multitude of base modi¯cations, which contribute to the natural processes of aging, mutagenesis and carcinogenesis. The stable products resulting from the main hydroxyl-radical-induced cytosine hydroperoxide, 5-hydroxy-6hydroperoxyl-5,6-dihydrocytosine (5-OH-6-OOH-DHC), have been mapped out in the present work for the¯rst time using ab initio calculations. Optimized geometries of all stationary structures in the gas phase were determined at the MP2 and B3LYP using the 6-31G(d) basis set and at the B3LYP/6-311þþG(d,p) levels of theory. Energies were also determined at the G3MP2 level of theory. Meanwhile, full optimization of all stationary points were also performed in aqueous solution at the B3LYP/CPCM/6-31G(d) level of theory to evaluate the solvent e®ect. Three distinct possible pathways, pathways AÀC, were evaluated. For pathway C, four channels, channels DÀG, were characterized in turn. In each pathway, both the direct and the water-mediated processes were considered. The calculated results clearly manifest that (i) pathway C is kinetically favored over pathways A and B and is the most energetically feasible decomposition process of 5-OH-6-OOH-DHC; (ii) for pathway C, channels D, E and G are energetically feasible mechanisms and 6,7-dihydroxy-[1,3,5]triazepane-2,4-dione, 1-carbamoyl-2-oxo-4,5-dihydroxyimidazolidine, and biuret therefore are predicted to be the kinetically favored decomposition products of 5-OH-6-OOH-DHC; (iii) channel G may be kinetically favored over channels D and E and have the highest possibility to occur; (iv) the thermal decomposition of 5-OH-6-OOH-DHC can be signi¯cantly promoted by the presence of one explicit water molecule. Apart from characterizing the experimental products well, the main striking result of the present DFT computational study is the identi¯cation of a new theoretical optimum decomposition product, i.e. 6,7-dihydroxy-[1,3,5]triazepane-2,4-dione. The data and insights presented here have elucidated the chemical properties of 5-OH-6-OOH-DHC in free radical reactions and should facilitate to assess their mutagenic features.

DFT study on addition reaction mechanism of guanine-cytosine base pair with OH radical

“…Most of the effects have belonged to the role of free radicals . It is known that free radicals constantly formed in living organisms by x‐rays, radiation therapy, and ultraviolet radiations could react with organic cellular components, such as protein, lipid, and nucleic acid . Especially, OH radical, as a highly reactive oxygen species, has an extremely short lifetime and plays a vital character for DNA damage .…”