Computational Study of the Deamination of 8-Oxoguanine

Abstract

Oxidation of guanine in DNA yields the nucleobase damage product 8-oxoguanine (8-oxoG), whose further oxidation gives other more stable products. In the present study, the mechanism for the deamination of 8-oxoG with H(2)O, 2H(2)O, H(2)O/OH(-), and 2H(2)O/OH(-) and for protonated 8-oxoG (8-oxoGH(+)) with H(2)O has been investigated using ab initio calculations. All structures were optimized at RHF/6-31G(d), MP2/6-31G(d), and B3LYP with the 6-31G(d), 6-31+G(d), 6-31G(d,p), 6-31+G(d,p), and 6-31++G(d.p) basis sets. Energies were determined at the G3MP2 level of theory, and solvent calculations were performed using both the polarizable continuum model (PCM) and the solvation model on density (SMD). Intrinsic reaction coordinate calculations were performed to characterize the transition states on the potential energy surface. Thermodynamic properties (ΔE, ΔH, and ΔG), activation energies, enthalpies, and Gibbs free energies of activation were also calculated for each reaction investigated. All pathways yield an initial tetrahedral intermediate and, in the final step, an intermediate that dissociates to products via a 1,3-proton shift. At the G3MP2 level of theory, deamination with H(2)O/OH(-) was found to have an overall activation energy of 187, 176, and 156 kJ mol(-1) for the gas phase, PCM, and SMD, respectively, which are ∼50 kJ mol(-1) lower than with H(2)O only. These barriers can be compared to those for the reaction of 8-oxoGH(+) with H(2)O of 248 kJ mol(-1) in the gas phase and 238 kJ mol(-1) in aqueous solution (PCM). The lowest overall activation energies (G3MP2) are for the deamination of 8-oxoG with 2H(2)O/OH(-), 134 kJ mol(-1) in the gas phase and 129 kJ mol(-1) with PCM.

A computational mechanistic study of the deamination reaction of melamine

“…Pathway F1 has the lowest overall activation energy of 201 kJ mol −1 compared to 232 kJ mol −1 for the pathway F2. The previous study of the deamination reaction of 8‐oxoguanine with 2H 2 O was found to be similar to this pathway where the overall activation energy is 220 kJ mol −1 at G3MP2 in the vacuum …”

“…Uddin et al found that the overall activation energy for the deamination of protonated guanine with H 2 O is 243 kJ mol −1 at G3MP2 . In another study, Uddin and Poirier found that the overall activation energy for deamination of protonated 8‐oxoguanine with H 2 O is 248 kJ mol −1 at G3MP2 which is in excellent agreement with energy barrier of protonated guanine . Yu et al studied the deamination reaction of protonated isoguanine with H 2 O, and they found that the overall activation energy is 217 kJ mol −1 at B3LYP/6‐311++G(d,p) .…”

“…The activation energy for deamination of melamine with H 2 O (pathways E1 and E2 ) are significantly higher than the reactions with OH – and n H 2 O/OH − , (where n = 1, 2, 3). The previous studies for the deamination reaction of cytosine, guanine, glutamine, 8‐oxoguanine, and isoguanine with one water molecule also give high energy barriers with the respective values of 221 at G3MP2, 187 at G3MP2, 180 at G3MP2B3, 233 at G3MP2, and 220 kJ mol −1 at B3LYP/6‐311++G(d,p).…”

“…In another study, for the deamination reaction of adenine to produce hypoxanthine, Alrawashdeh et al found that adding an additional water molecule reduces the energy barrier of the reaction . Furthermore, a computational study of the deamination reaction of 8‐oxoguanine with 2H 2 O/OH − showed that the lowest overall activation energy is 134 kJ mol −1 at G3MP2 in the vacuum and 129 kJ mol −1 with PCM solvation model …”

Hydrolytic deamination reactions of amidine and nucleobase derivatives

“…[14] Besides experimental reports, computational studies have also been performed on the deamination reactions of amidine and nucleobases derivatives. [4,13,[27][28][29][30][31][32][33][34][35][36][37] Flinn and Poirier [4] carried out an extensive computational study on the catalytic deamination of formamidine with H 2 due to high activation energy barriers (> 210 kJ mol -1 at G2 theory) involved. For the deamination of formamidine with OH − , their results showed that deprotonation of formamidine by OH − , rather than deamination, is the most likely process.…”