DFT study of adenine‐uracil base pair damage by OH radical

Abstract

The hydrogen abstraction and addition reactions of OH radical with A·U base pair have been explored by using density functional theory (DFT) both in gas phase and in aqueous solution. Solvent effects were taken into consideration by using the polarized continuum model. All the reaction pathways are exothermic in energy, and the compounds in aqueous phase are more favorable than those in gas phase. The relative free energies of adducts in the addition reaction are lower than those obtained for products in hydrogen abstraction reaction. Among dehydrogenation reaction, the hydrogen abstractions from AC2·U and AN6·U sites are more favorable than those from AC8·U, A·UC5, and A·UC6 sites. In addition, hydroxylation at AC8·U, A·UC5, and A·UC6 sites are more probable than other investigated positions. The hydroxylation at AH8·U site is most favorable, and hydroxylation at A·UC5 site is more preference than that at A·UC6 site controlled by the kinetics factors. The data in both gas phase and water solution demonstrated that addition of OH radical to A·UC5 and A·UC6 sites are more thermodynamically and kinetically favorable than abstracting the hydrogen atom form A·UC5 and A·UC6 sites. The phenomena are in agreement with the experimental observations. Copyright © 2015 John Wiley & Sons, Ltd.

Mechanism of the OH Radical Addition to Adenine from Quantum-Chemistry Determinations of Reaction Paths and Spectroscopic Tracking of the Intermediates

“…The first analysis indicates that the result is independent from the theoretical method. Thus, accurate electronic structure calculations [see CCSD­(T)-(PCM)//M06-2X-(PCM) results below, Table )] and previous computations with different functionals , corroborate the energy trend. Second, explicit solvation has been modeled at the DFT/M06-2X-(PCM) level including six molecules of water localized in the plane of A .…”

“…Early experimental works proposed that addition to C4 position is the preferred pathway, [16][17][18]25 whereas theoretical estimations favor the C5 position. 34,39 In the present paper, we report evidence that supports a more favorable and competitive addition to the C5 and C8 positions, and we clearly demonstrate that the C4 channel must be considered a significantly minor pathway. Optical changes at ∼400 nm are explained in terms of the oxidation/reduction of the ringopened A8OH derivatives, while the intense band recorded at ∼330 nm is mainly assigned to the absorbance of ANH species.…”

“…The first analysis indicates that the result is independent from the theoretical method. Thus, accurate electronic structure calculations [see CCSD(T)-(PCM)//M06-2X-(PCM) results below, Table 3)] and previous computations with different functionals 34,39 molecules in the system), which could lead to a differential solvation of the TSs, has been appraised by computing the potential energy surface along the C−H 2 O coordinate as displayed in Figures S4 and S5. Very small stabilizations (−1.13 vs −0.87 kcal/mol) have been computed for the systems, confirming the preference for the C5 channel.…”

Regioselectivity of the OH Radical Addition to Uracil in Nucleic Acids. A Theoretical Approach Based on QM/MM Simulations

“…Because of the aforementioned relevance, the reaction between DNA/RNA and the • OH has been largely studied in the fields of chemistry, physics, and biology. ,− It has been concluded that nucleobases are important targets of this radical and that • OH reacts via hydrogen abstractions or addition reactions onto the double bonds. ,− However, the mechanism, in particular, the regioselectivity, is still an issue of some discrepancies among experimental studies and theoretical works using distinct methodologies. ,, …”

“…In uracil, theoretical − ,, and experimental ,− works have concluded that OH radical addition to the double bond is more favorable than hydrogen abstraction. In the addition reaction, two adducts can be produced depending on the OH radical attack, which can take place either to the C5 atom or to the C6 atom, giving rise to the U5OH • or U6OH • , respectively (see Scheme ).…”