One-Electron Oxidation of Neutral Sugar Radicals of 2′-Deoxyguanosine and 2′-Deoxythymidine: A Density Functional Theory (DFT) Study

Abstract

One electron oxidation of neutral sugar radicals has recently been suggested to lead to important intermediates in the DNA damage process culminating in DNA strand breaks. In this work, we investigate sugar radicals in a DNA model system to understand the energetics of sugar radical formation and oxidation. The geometries of neutral sugar radicals C1′•, C2′•, C3′•, C4′• and C5′• of 2′-deoxyguanosine (dG) and 2′-deoxythymidine (dT) were optimized in the gas phase and in solution using the B3LYP and ωB97x functionals and 6-31++G(D) basis set. Their corresponding cations (C1′+, C2′+, C3′+, C4′+ and C5′+) were generated by removing an electron (one-electron oxidation) from the neutral sugar radicals and their geometries were also optimized using the same methods and basis set. The calculation predicts the relative stabilities of the neutral sugar radicals in the order C1′• > C4′• > C5′• > C3′• > C2′•, respectively. Of the neutral sugar radicals, C1′• has the lowest vertical ionization potential (IPvert) ca. 6.33 eV in the gas phase and 4.71 eV in solution. C2′• has the highest IPvert ca. 8.02 eV in the gas phase and the resultant C2′ cation is predicted to undergo a barrierless hydride transfer from the C1′ site to produce the C1′ cation. One electron oxidation of C2′• in dG is predicted to result in a low lying triplet state consisting of G+• and C2′•. The 5′,8-cyclo-2′-deoxyguanosin-7-yl radical formed by intramolecular bonding between C5′• and C8 of guanine transfers spin density from C5′ site to guanine and this structure has IPvert 6.25 eV and 5.48 eV in the gas phase and in solution.

Gamma and ion-beam irradiation of DNA: Free radical mechanisms, electron effects, and radiation chemical track structure

“…This experimental observation was supported by our calculation of the energy of C2′ + within dGuo sing the ω 97x/6-31++G(d) method with PCM. Our calculation showed that geometry optimization of C2′ + proceeds on a barrierless surface to produce C1′ + by transferring a hydrogen from C1′ to C2′, see Figure 2d in reference Kumar et al, 2012b.…”

“…The simulated spectrum assumed axial symmetry and employed the following parameters: A ⊥ = 775 G, A || = 610 G, g ⊥ = 2.00, g || = 2.01 and linewidth = 12 G. The origin of these radicals is suggested by the fact that LEEs are known to create strand breaks in DNA by dissociative electron attachment (DEA) (Boudaïffa et al, 2000). Thus, LEE can form both C3′• dephos and ROPO 2 • − by DEA at the sugar phosphate backbone (scheme 2) (Kumar and Sevilla, 2009, 2012; Adhikary et al, 2014a). …”

“…Since LEEs are formed both in the core and penumbra, these results suggest that other factors, such as, excited electronic states or excited vibrational modes add to the effectiveness of LEE in the core. In this regard, we note that theoretical calculations show that stretching of the C-O bond in the sugar-phosphate backbone (as would occur in excited vibrational modes) leads to electron capture into a dissociative state leading to a strand break (Li et al, 2003, Kumar and Sevilla., 2008, 2009, Kumar and Sevilla., 2012). …”

“…In contrast, for oxidatively damaged DNA, C1′• was found to be preferred (Roginskaya et al, 2005a, 2005b; Xue and Greenberg, 2007). In general, the relative stability of neutral sugar radicals, calculated using theory, follow the order C1′• > C4′• > C5′• > C3′• > C2′• (Kumar et al, 2012b; Li et al, 2006; Miaskiewicz and Osman, 1994). …”

“…The B3LYP and ωB97x calculated gas phase IP of C2′• and of dGuo lie in the range 8.02 eV – 8.72 eV which is comparable to the calculated gas phase IP (7.99 – 8.14 eV) of guanine, however, for Thd the gas phase IP of C2′• is lower than the thymine base by ca. 0.2 –0.5 eV (Kumar et al, 2012b). …”