Computational Study of the pH-Dependent Competition between Carbonate and Thymine Addition to the Guanine Radical

Hebert, Sebastien P.; Schlegel, H. Bernhard

doi:10.1021/acs.chemrestox.8b00302

Cited by 11 publications

(12 citation statements)

References 117 publications

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“…4 was calculated to have a reduction potential of 0.05 V and −0.14 V with DFT and CBS-QB3, respectively, compared to −0.16 V for triplet oxygen, suggesting oxidation with 3 O 2 would be only slightly endothermic. C8 deprotonation was calculated to be significantly more exothermic after oxidation, 55 allowing the pathway to continue forward to the 8oxoG product. 5 was calculated to have a reduction potential of 0.73 V calculated with DFT and 0.64 V with CBS-QB3, suggesting 3 O 2 oxidation would be about 18−23 kcal/mol endothermic and a stronger oxidant would be required.…”

Section: Resultsmentioning

confidence: 99%

“…While many studies have found 2Ih, − ,,− the mechanistic pathways for its formation are not well understood. In previous studies, we have used density functional calculations to explore mechanisms for guanine oxidation to form 8oxoG, Sp, Gh, and FAPyG, − formation of guanine-lysine cross-links mediated by type I and type II photosensitizers , and by sulfate radical, and formation of guanine-thymine cross-link products . We have also calculated p K a s and reduction potentials for nucleobases and intermediates in the guanine oxidation mechanism. − In this computational study, we address pathways leading to 2Ih.…”

Section: Introductionmentioning

confidence: 99%

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Computational Study of the Oxidation of Guanine To Form 5-Carboxyamido-5-formamido-2-iminohydantoin (2Ih)

Hebert

Schlegel

2019

Chem. Res. Toxicol.

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Oxidative damage to DNA leads to a number of two-electron oxidation products of guanine such as 8-oxo-7,8-dihydroguanine (8oxoG). 5-Carboxyamido-5-formamido-2-iminohydantoin (2Ih) is another two-electron oxidation product that forms in competition with 8oxoG. The pathways for the formation of 2Ih have been studied by density functional theory using the ωB97XD functional with the 6-31+G(d,p) basis set and SMD implicit water solvation plus a small number of explicit water molecules positioned to help stabilize charged species and facilitate reaction steps. For oxidative conditions that produce hydroxyl radical, such as Fenton chemistry, hydroxy radical can add at C4, C5, or C8. Addition at C4 or C5 followed by loss of H2O produces guanine radical. Guanine radical can also be produced directly by oxidation of guanine by reactive oxygen species (ROS). A C5-OH intermediate can be formed by addition of superoxide to C5 of guanine radical followed by reduction. Alternatively, the C5-OH intermediate can be formed by hydroxy radical addition at C5 and oxidation by 3O2. The competition between oxidative and reductive pathways depends on the reaction conditions. Acyl migration of the C5-OH intermediate yields reduced spiroiminodihydantoin (Spred). Subsequent water addition at C8 of Spred and N7–C8 ring opening produces 2Ih. Hydroxy radical addition at C8 can lead to a number of products. Oxidation and tautomerization produces 8oxoG. Alternatively, addition of superoxide at C5 and reduction results in a C5, C8 dihydroxy intermediate. For this species, the low energy pathway to 2Ih is N7–C8 ring opening followed by acyl migration. Ring opening occurs more easily at C8–N9 but leads to a higher energy analogue of 2Ih. Thus, the dominant pathway for the production of 2Ih depends on the nature of the reactive oxygen species and on the presence or absence of reducing agents.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Computational Study of the Oxidation of Guanine To Form 5-Carboxyamido-5-formamido-2-iminohydantoin (2Ih)

Hebert

Schlegel

2019

Chem. Res. Toxicol.

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“…Explicit waters were included as a supplement to the implicit model, as in previous studies. 65,66 Guanine was capped with a methyl group in place of the N9-bound sugar moiety.…”

Section: Methodsmentioning

confidence: 99%

“…All calculations were performed using the development version of the Gaussian series of programs and the ωB97XD density functional with the 6-31+G(d,p) basis set. − SMD implicit water solvation was used to model aqueous conditions. Explicit waters were included as a supplement to the implicit model, as in previous studies. , Guanine was capped with a methyl group in place of the N9-bound sugar moiety.…”

Section: Methodsmentioning

confidence: 99%

Computational Investigation into the Oxidation of Guanine to Form Imidazolone (Iz) and Related Degradation Products

Hebert

Schlegel

2020

Chem. Res. Toxicol.

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Imidazolone (Iz) is one of the many products resulting from oxidative damage to DNA. Three pathways for the formation of Iz and related degradation products have been studied by density functional theory using the ωB97XD functional with the 6-31+G(d,p) basis set and SMD implicit water solvation plus a small number of explicit water molecules positioned to help stabilize charged species and facilitate reaction steps. The first pathway starts with guanine radical and the addition of superoxide at C5. Endoperoxide formation was calculated to have slightly lower barriers than diol formation. The next steps are pyrimidine ring opening and decarboxylation. Ring migration then proceeds via an acyclic intermediate rather than a bicyclic intermediate and is followed by formamide loss to yield Iz. The second pathway starts with 8oxoG and proceeds via C5 superoxide addition and diol formation to a relatively stable intermediate, oxidized guanidinohydantoin (Ghox). The barriers for hydroxide ion addition to Ghox are much lower than for water addition and should yield more Iz and parabanic acid at higher pH. The third pathway starts with 8-hydroxy guanine radical formed by hydroxyl radical addition to C8 of guanine or water addition to C8 of guanine radical. Superoxide addition at C5 is followed by diol formation, ring opening and decarboxylation similar to pathways 1 and 2, subsequently leading to Iz formation. The calculated pathways are in good agreement with experimental observations.

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“…A great deal of research studies have investigated cytosine, its nucleosides and nucleotides, and many of its other derivatives using both experimental and theoretical approaches in both the gas and aqueous phases. ,− The studies about the electron attachment to the cytosine-centered DNA have been reported. In the DNA oligomers, excess electrons may be located at different sites, forming various radical anions.…”

Section: Introductionmentioning

confidence: 99%

Intriguing Radical–Radical Interactions in Doubly Reduced Dimers: Cytosine Anion Radical versus Hydrogenated Cytosine Radical

Zhao

Wang

et al. 2020

J. Phys. Chem. C

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In the present work, we computationally investigate a series of the homogeneous and heterogeneous base dimers of the reduced cytosine (single-electron-reduced C•– and 5/6/3-site hydrogenated CH5•/CH6•/CH3•), including C•–C•–, CH5•CH5•, CH6•CH6•, CH6•CH5•, CH3•CH3•, CH5•C•–, and CH6•C•–, and explore their structures, electronic, and magnetic spin coupling properties by the density functional theory method. Different coupling modes (Watson–Crick/WC, Hoogsteen/Hoog, and minor groove/min hydrogen bonding, and π–π stacking modes) are considered. The double-electron reduction can destabilize the CC unit to be a metastable state with an unexpected barrier-hindered dissociation channel featuring negative dissociation energy. This novel energetic phenomenon of the negative dissociation energy for C•–C•–, (CH5•CH5•)CS, (CH6•CH6•)CS, and (CH5•CH6•)CS originates from the competition of two interactions between the electrostatic repulsion and H-bonding attraction. More interestingly, these double-electron-reduced H-bonded CC (C•–C•–, CH5•CH5•, CH6•CH6•, CH6•CH5•, and CH3•CH3•) base dimers have the well-defined diradical characters and exhibit variable degrees of intramolecular magnetic exchange interaction (ferromagnetic/FM, antiferromagnetic/AFM, or nonmagnetic). The magnetic coupling interactions of some doubly reduced CC base pairs are controlled by H-bonding, electrostatic repulsion, and radical coupling interaction. The π–π stacked (CH5•CH5•)ππ, (CH6•CH6•)ππ, (CH6•CH5•)ππ, and (CH3•CH3•)ππ also exhibit various degrees of FM and AFM characters. Almost all of them possess the AFM spin coupling characteristics, except for (CH5•CH5•)ππ cr, (CH5•CH5•)ππ cl, and (CH3•CH3•)ππ ap, which display the FM spin coupling characteristics. Clearly, this work provides the first theoretical prediction of useful information about the electronic properties of possible doubly reduced CC base pairs.

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Computational Study of the pH-Dependent Competition between Carbonate and Thymine Addition to the Guanine Radical

Cited by 11 publications

References 117 publications

Computational Study of the Oxidation of Guanine To Form 5-Carboxyamido-5-formamido-2-iminohydantoin (2Ih)

Computational Study of the Oxidation of Guanine To Form 5-Carboxyamido-5-formamido-2-iminohydantoin (2Ih)

Computational Investigation into the Oxidation of Guanine to Form Imidazolone (Iz) and Related Degradation Products

Intriguing Radical–Radical Interactions in Doubly Reduced Dimers: Cytosine Anion Radical versus Hydrogenated Cytosine Radical

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