Base Pair Radical Research Articles

Effects of Intra-Base Pair Proton Transfer on Dissociation and Singlet Oxygenation of9-Methyl-8-Oxoguanine-1-Methyl-Cytosine Base-Pair Radical Cations.

8-Oxoguanosine is the most common oxidatively generated base damage and pairs with cytidine within duplex DNA. The 8-oxoguanosine-cytidine lesion, if not recognized and removed, not only leads to G-to-T transversion mutations but renders the base pair being more vulnerable to the ionizing radiation and singlet oxygen (1O2) damage. Herein, reaction dynamics of a prototype Watson-Crick base pair [9MOG·1MC]·+, consisting of 9-methyl-8-oxoguanine radical cation (9MOG·+) and 1-methylcystosine (1MC), was examined using mass spectrometry coupled with electrospray ionization. We first detected base-pair dissociation in collisions with the Xe gas, which provided insight into intra-base pair proton transfer of 9MOG·+·1MC[[EQUATION]][9MOG - HN1]··[1MC + HN3']+ and subsequent non-statistical base-pair separation. We then measured the reaction of [9MOG·1MC]·+ with 1O2, revealing the two most probable pathways, C5-O2 addition and HN7-abstraction at 9MOG. Reactions were entangled with the two forms of 9MOG radicals and base-pair structures as well as multi-configurations between open-shell radicals and 1O2 (that has a mixed singlet/triplet character). These were disentangled by utilizing approximately spin-projected density functional theory, coupled-cluster theory and multi-referential electronic structure modeling. The work delineated base-pair structural context effects and determined relative reactivity toward 1O2 as [9MOG - H]· > 9MOG·+ > [9MOG - HN1]··[1MC + HN3']+ ≥ 9MOG·+·1MC.

Development of a Double-Well Potential upon Collisional Activation that Facilitates Proton Transfer in 9-Methyl-8-oxoguanine-9-Methyladenine Base-Pair Radical Cation

Development of a Double-Well Potential upon Collisional Activation that Facilitates Proton Transfer in 9-Methyl-8-oxoguanine-9-Methyladenine Base-Pair Radical Cation

Collision-induced dissociation of homodimeric and heterodimeric radical cations of 9-methylguanine and 9-methyl-8-oxoguanine: correlation between intra-base pair proton transfer originating from the N1-H at a Watson-Crick edge and non-statistical dissociation.

It has been shown previously in protonated, deprotonated and ionized guanine-cytosine base pairs that intra-base pair proton transfer from the N1-H at the Watson-Crick edge of guanine to the complementary nucleobase prompts non-statistical dissociation of the base-pair system, and the dissociation of a proton-transferred base-pair structure is kinetically more favored than that of the starting, conventional base-pair structure. However, the fundamental chemistry underlying this anomalous and intriguing kinetics has not been completely revealed, which warrants the examination of more base-pair systems in different structural contexts in order to derive a generalized base-pair structure-kinetics correlation. The purpose of the present work is to expand the investigation to the non-canonical homodimeric and heterodimeric radical cations of 9-methylguanine (9MG) and 9-methyl-8-oxoguanine (9MOG), i.e., [9MG·9MG]˙+, [9MOG·9MG]˙+ and [9MOG·9MOG]˙+. Experimentally, collision-induced dissociation tandem mass spectrometry coupled with an electrospray ionization (ESI) source was used for the formation of base-pair radical cations, followed by detection of dissociation product ions and cross sections in the collisions with Xe gas under single ion-molecule collision conditions and as a function of the center-of-mass collision energy. Computationally, density functional theory and coupled cluster theory were used to calculate and identify probable base-pair structures and intra-base pair proton transfer and hydrogen transfer reactions, followed by kinetics modeling to explore the properties of dissociation transition states and kinetic factors. The significance of this work is twofold: it provides insight into base-pair opening kinetics in three biologically-important, non-canonical systems upon oxidative and ionization damage; and it links non-statistical dissociation to intra-base pair proton-transfer originating from the N1-H at the Watson-Crick edge of 8-oxoguanine, enhancing understanding towards the base-pair fragmentation assisted by proton transfer.

The reduction potential of the slipped GC base pair in one-electron oxidized duplex DNA.

Redox equilibrium between the low potential aniline radical cation and the guanine in the GC base pair of duplex DNA has been established using pulse radiolysis. We relate the measurement of a radical one-electron reduction potential, E0', of 1.01 ± 0.03 V to the perturbation of the GC base pair to accommodate the neutral guanyl radical in an energetically more stable 'slipped' structure. The formation of the 'slipped' structure is exothermic by -11.4 kcal mol-1 as calculated by DFT, which is inline with our experimental results.

Mass spectrometry and computational study of collision-induced dissociation of 9-methylguanine-1-methylcytosine base-pair radical cation: intra-base-pair proton transfer and hydrogen transfer, non-statistical dissociation, and reaction with a water ligand.

A combined experimental and theoretical study is presented on the collision-induced dissociation (CID) of 9-methylguanine-1-methylcytosine base-pair radical cation (abbreviated as [9MG·1MC]˙+) and its monohydrate ([9MG·1MC]˙+·H2O) with Xe and Ar gases. Product ion mass spectra were measured as a function of collision energy using guided-ion beam tandem mass spectrometry, from which cross sections and threshold energies for various dissociation pathways were determined. Electronic structure calculations were performed at the DFT, RI-MP2 and DLPNO-CCSD(T) levels of theory to identify product structures and map out reaction potential energy surfaces. [9MG·1MC]˙+ has two structures: a conventional structure 9MG˙+·1MC (population 87%) consisting of hydrogen-bonded 9-methylguanine radical cation and neutral 1-methylcytosine, and a proton-transferred structure [9MG - H]˙·[1MC + H]+ (less stable, population 13%) formed by intra-base-pair proton transfer from the N1 of 9MG˙+ to the N3 of 1MC within 9MG˙+·1MC. The two structures have similar dissociation energies but can be distinguished in that 9MG˙+·1MC dissociates into 9MG˙+ and 1MC whereas [9MG - H]˙·[1MC + H]+ dissociates into neutral [9MG - H]˙ radical and protonated [1MC + H]+. An intriguing finding is that, in both Xe- and Ar-induced CID of [9MG·1MC]˙+, product ions were overwhelmingly dominated by [1MC + H]+, which is contrary to product distributions predicted using a statistical reaction model. Monohydration of [9MG·1MC]˙+ reversed the populations of the conventional structure (43%) vs. the proton-transferred structure (57%) and induced new reactions upon collisional activation, of which intra-base-pair hydrogen transfer produced [9MG + H]+ and the reaction of the water ligand with a methyl group in [9MG·1MC]˙+ led to methanol elimination from [9MG·1MC]˙+·H2O.

Watson-Crick Base Pair Radical Cation as a Model for Oxidative Damage in DNA.

The deleterious cellular effects of ionizing radiation are well-known, but the mechanisms causing DNA damage are poorly understood. The accepted molecular events involve initial oxidation and deprotonation at guanine sites, triggering hydrogen atom abstraction reactions from the sugar moieties, causing DNA strand breaks. Probing the chemistry of the initially formed radical cation has been challenging. Here, we generate, spectroscopically characterize, and examine the reactivity of the Watson-Crick nucleobase pair radical cation in the gas phase. We observe rich chemistry, including proton transfer between the bases and propagation of the radical site in deoxyguanosine from the base to the sugar, thus rupturing the sugar. This first example of a gas-phase model system providing molecular-level details on the chemistry of an ionized DNA base pair paves the way toward a more complete understanding of molecular processes induced by radiation. It also highlights the role of radical propagation in chemistry, biology, and nanotechnology.

UV-Induced Proton Transfer between DNA Strands.

UV radiation creates excited states in DNA that lead to mutagenic photoproducts. Photoexcitation of single-stranded DNA can transfer an electron between stacked bases, but the fate of excited states in the double helix has been intensely debated. Here, photoinduced interstrand proton transfer (PT) triggered by intrastrand electron transfer (ET) is detected for the first time by time-resolved vibrational spectroscopy and quantum mechanical calculations. Long-lived excited states are shown to be oppositely charged base pair radical ions. In two of the duplexes, the base pair radical anions are present as tautomers formed by interstrand PT. Charge recombination occurs on the picosecond time scale preventing the accumulation of damaging radicals or mutagenic tautomers.

Effect of nucleobase sequence on the proton-transfer reaction and stability of the guanine–cytosine base pair radical anion

The formation of base pair radical anions is closely related to many fascinating research fields in biology and chemistry such as radiation damage to DNA and electron transport in DNA. However, the relevant knowledge so far mainly comes from studies on isolated base pair radical anions, and their behavior in the DNA environment is less understood. In this study, we focus on how the nucleobase sequence affects the properties of the guanine-cytosine (GC) base pair radical anion. The energetic barrier and reaction energy for the proton transfer along the N(1)(G)-H···N(3)(C) hydrogen bond and the stability of GC˙(-) (i.e., electron affinity of GC) embedded in different sequences of base-pair trimer were evaluated using density functional theory. The computational results demonstrated that the presence of neighboring base pairs has an important influence on the behavior of GC˙(-) in the gas phase. The excess electron was found to be localized on the embedded GC and the charge leakage to neighboring base pairs was very minor in all of the investigated sequences. Accordingly, the sequence behavior of the proton-transfer reaction and the stability of GC˙(-) is chiefly governed by electrostatic interactions with adjacent base pairs. However, the effect of base stacking, due to its electrostatic nature, is severely screened upon hydration, and thus, the sequence dependence of the properties of GC˙(-) in aqueous environment becomes relatively weak and less than that observed in the gas phase. The effect of geometry relaxation associated with neighboring base pairs as well as the possibility of proton transfer along the N(2)(G)-H···O(2)(C) channel have also been investigated. The implications of the present findings to the electron transport and radiation damage of DNA are discussed.

Microhydration of 9-methylguanine:1-methylcytosinebase pair and its radical anion: a density functional theory study

In this study, we present density functional theory calculations on the properties of proton transfer and electron binding in isolated, mono-, di-, and pentahydrated 9-methylguanine:1-methylcytosine (mG:mC) base pair radical anions. It was found that the proton transfer in mG:mC(*-) is coupled to the interbase propeller-twisting and stretching motions, which cooperatively shorten the proton-transfer distance. Without the propeller-twisting motion, the interbase stretching will be hindered and the proton-transfer distance will become somewhat longer, which in turn, results in rising of the kinetic barrier for proton transfer. The monohydration can assist or resist the proton-transfer reaction, depending on the hydration sites. Inclusion of five water molecules in the first hydration shell around mG:mC(*-) only moderately lowers the proton-transfer barrier from 3.80 to 3.01 kcal mol(-1) and the reaction energy from -3.16 to -6.40 kcal mol(-1) due to the cancellation between opposite influences of H(2)O molecules. A further consideration of bulk hydration using a polarizable continuum model does not affect the proton-transfer energetics. In contrast, both the first hydration shell and bulk hydration were found to play important roles in stabilizing the excess electron in mG:mC; the adiabatic electron affinity of mG:mC increases from 0.302 to 0.645 eV upon inclusion of five water molecules in the first hydration shell, and further increases to 1.813 eV when the bulk hydration is considered. We noticed that the water molecule can enhance electron binding by direct interaction with the nucleobase that accommodates excess electron or through the indirect effect of tuning interbase hydrogen bonds. In addition, the microhydration effects on proton transfer and electron binding were found to be approximately additive.

Proton Transfer in Guanine−Cytosine Radical Anion Embedded in B-Form DNA

The electron-attachment-induced proton transfer in the guanine-cytosine (G:C) base pair is thought to be relevant to the issues of charge transport and radiation damage in DNA. However, our understanding on the reaction mainly comes from the data of isolated bases and base pairs, and the behavior of the reaction in the DNA duplex is not clear. In the present study, the proton-transfer reaction in reduced G:C stacks is investigated by quantum mechanical calculations with the aim to clarify how each environmental factor affects the proton transfer in G:C(*-). The calculations show that while the proton transfer in isolated G:C(*-) is exothermic with a small energetic barrier, it becomes endothermic with a considerably enhanced energetic barrier in G:C stacks. The substantial effect of G:C stacking is proved to originate from the electrostatic interactions between the dipole moments of outer G:C base pairs and the middle G:C(*-) base-pair radical anion; the extent of charge delocalization is very small and plays little role in affecting the proton transfer in G:C(*-). On the basis of the electrostatic model, the sequence dependence of the proton transfer in the ionized G:C base pair is predicted. In addition, the water molecules in the first hydration shell around G:C(*-) display a pronounced effect that facilitates the proton-transfer reaction; further consideration of bulk hydration only slightly lowers the energetic barrier and reaction energy. We also notice that the water arrangement around an embedded G:C(*-) is different from that around an isolated G:C(*-), which could result in a very different solvent effect on the energetics of the proton transfer. In contrast to the important influences of base stacking and hydration, the effects of sugar-phosphate backbone and counterions are found to be minor. Our calculations also reveal that a G:C base pair embedded in DNA is capable of accommodating two excess electrons only in bulk hydration; the resultant G(N1-H)(-):C(N3+H)(-) dianion is stable and exists long enough to lead to DNA damage. The combination of the present results with the previous findings in literature suggests that the behaviors of charge transport and low-energy electron-induced damage in DNA are highly susceptible to the hydration level.

Elementary Lesions in DNA Subunits: Electron, Hydrogen Atom, Proton, and Hydride Transfers

When DNA is damaged by ionizing radiation, the genes in a cell may acquire mutations or the cell could die. The smallest known DNA-damaging unit is an electron, often low-energy secondary electrons. Additional electrons and transfers involving hydrogen atoms, protons, and hydride anions can damage DNA subunits, including individual nucleobases and nucleoside pairs. Researchers would like to better understand the molecular mechanisms involved in DNA damage from ionizing radiation. In this Account, we highlight our theoretical investigations of the molecular mechanisms of DNA damage using quantum mechanical models. Our investigations use robust theoretical methods with computations conducted in the gas phase and with solution models. We calculate adiabatic electron affinities (AEAs), which describe the energetics of electronic attachment to closed-shell DNA subunits, for the free bases, nucleosides, nucleotides, base pairs, and single and double DNA strand units. Electron affinities for free nucleobases yield the order uracil > thymine > cytosine > guanine > adenine and the same order for the DNA nucleosides, mononucleotides, and nucleoside 3',5'-diphosphates. AEA values increase steadily with the size and complexity of the system because of greater hydration, glycosylation, nucleotide formation, and base pairing. We predict and experimental results partially confirm that most of the more complex and hydrated species are observable as radical anions. Our modeling studies indicate that depyrimidination reactions of radical anion nucleosides release cytosine more often than thymine. Recent experimental results support those findings. Our theoretical studies of DNA base-pair radical anions predict increases in electron affinity accompanying H bonding and solvation. Electron addition facilitates some proton transfers in these pairs, which results in strongly perturbed pairing configurations. Of all nucleobase moieties within the more complex radical anion systems, thymine is best able to retain a negative charge. Charge and spin are well-separated in some of these systems. Radical species derived via hydrogen abstraction from DNA subunits yield large AEA values because they form closed-shell anions. Our studies predict single-strand breaks following H abstraction from nucleotides. Some H-abstraction processes in the DNA base pairs lead to severe distortions in pairing configuration based on our calculations. This body of systematic theoretical studies provides realistic descriptions of some events that lead to elementary DNA lesions, while providing rationalizations for many observed phenomena. Such approaches can lead to the design of new experiments, which would contribute to our understanding of the chemical physics of nucleic acids.

Molecular Structures and Energetics Associated with Hydrogen Atom Addition to the Guanine-Cytosine Base Pair.

The radicals generated by hydrogen-atom addition to the Watson-Crick guanine-cytosine (G-C) DNA base pair were studied theoretically using an approach that has proved effective in predicting molecular structures and energetics. All optimized structures were confirmed to be minima via vibrational frequency analysis. The dissociation energies of the base-pair radicals are predicted and compared with that of the neutral G-C base pair. The lowest-energy base-pair radical is that with the hydrogen atom attached to the C8 position of guanine, resulting in the nitrogen radical designated G(C8)-C. In this, the most favorable radical, the G-C pair C8 [Formula: see text] N7 distance of 1.310 Å increases to 1.453 Å when the π bond is broken upon hydrogen-atom addition. This radical has a dissociation energy of 28 kcal/mol, which may be compared with 27 kcal/mol for neutral G-C. The other (GC + H)(•) radical dissociation energies range downward to 8 kcal/mol. Significant structural changes were observed when the hydrogen was added to the sites where the interstrand hydrogen bonds are formed. For example, "butterfly"-shape structures were found when the hydrogen atom was added to the C4 or C5 sites of guanine. The formation of radical G(C2)-C may cause a single-strand break because of significant strain in the closely stacked base pairs. Radical G(C8)-C is of biological importance because it may be an intermediate in the formation of 8-oxo guanine.

(G–H) • –C and G–(C–H) • radicals derived from the guanine·cytosine base pair cause DNA subunit lesions

The radicals generated by the homolytic cleavage of an X–H bond from the guanine·cytosine (G·C) base pair were studied by using carefully calibrated theoretical methods. The gradient-corrected density functional B3LYP was applied in conjunction with double-ζ plus polarization and diffuse function basis sets. Optimized geometries, energies, and vibrational frequencies were obtained for all of the radicals considered. Structural perturbations along with energy relaxation due to radical formation were investigated. Dissociation energies of the G·C base pair and all of the radicals are predicted and compared with the dissociation energy of neutral G·C. The three lowest-energy base pair radicals all involve removal of an H atom from one of the N atoms in G·C. The lowest-energy base pair radical has the hydrogen atom removed from the guanine nitrogen atom used for the sugar phosphate linkage in DNA. This (G–H) • –C radical has a dissociation energy (to G–H • + C) of 30 kcal/mol, which may be compared with 27 kcal/mol for G·C. All of the radicals that are possible outcomes of direct ionizing radiation or oxidizing species were investigated for the presence of local minima with significant structural changes. Major structural deformations cause strain in the interstrand hydrogen bonding in the DNA double helix. Severe geometry changes were observed when the hydrogen was abstracted from interstrand hydrogen bonding sites, along with sizeable energy changes, indicating the potentially serious consequences to the G·C base pair.

The Adenine−Thymine Base Pair Radical Anion: Adding an Electron Results in a Major Structural Change

The adiabatic electron affinity (AEA) for the Watson−Crick adenine−thymine (AT) DNA base pair is predicted and contrasted to that of guanine−cytosine (GC) with a range of density functional methods with double- and triple-ζ plus polarization plus diffuse (DZP++ and TZ2P++) basis sets. An estimate of the true AEA is provided using a bracketing method that has been calibrated against a comprehensive tabulation of experimental electron affinities [Rienstra-Kiracofe, J. C.; Tschumper, G. S.; Schaefer, H. F.; Nandi, S.; Ellison, G. B. Chem. Rev. 2002, 102, 10163]. Optimized structures for AT and the AT anion are compared to the neutral and anionic forms of the individual bases as well as Rich's 1976 X-ray structure for the related sodium adenylyl-3‘,5‘-uridine hexahydrate, ApU·6H2O. In contrast to the angular distortions (to nonplanarity) occurring in GC upon anion formation, the angular distortions for the AT anion are slight. However, in an analogous fashion to the GC anion, major changes in the AT anion hyd...

Ab initio molecular orbital calculations on DNA base pair radical ions: effect of base pairing on proton-transfer energies, electron affinities, and ionization potentials

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTAb initio molecular orbital calculations on DNA base pair radical ions: effect of base pairing on proton-transfer energies, electron affinities, and ionization potentialsAnny Odile Colson, Brent Besler, and Michael D. SevillaCite this: J. Phys. Chem. 1992, 96, 24, 9787–9794Publication Date (Print):November 1, 1992Publication History Published online1 May 2002Published inissue 1 November 1992https://doi.org/10.1021/j100203a039RIGHTS & PERMISSIONSArticle Views441Altmetric-Citations125LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (1 MB) Supporting Info (1)»Supporting Information Supporting Information Get e-Alerts

ChemInform Abstract: Ab initio Molecular Orbital Calculations of DNA Bases and Their Radical Ions in Various Protonation States: Evidence for Proton Transfer in GC Base Pair Radical Anions.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Ab initio molecular orbital calculations of DNA bases and their radical ions in various protonation states: evidence for proton transfer in GC base pair radical anions

Ab initio molecular orbital calculations of various protonation states of DNA base and DNA base radical ions were performed to aid our understanding of primary radiation processes in DNA. Each of the structures was optimized at the STO-3G and 3-21 levels of theory, and single point calculations were performed at the 6-31G*//3-21G and 6-31+G(d)//3-21G levels. Each of the protonation states important to proton-transfer reactions in base pair radical ions found in irradiated DNA was considered. Calculations for three protonation states for the cytosine reduced radical were performed and the most stable is found to be the N-3 ring-protonated species. Calculations for the vertical ionization energies of the individual DNA bases yielded the following order T>C>A>G with the same order found for the adiabatic electron affinities of the bases. The best fit to experiment was found with Koopmans` theorem ionization potentials. The energy for proton transfer in the GC and AT base pair radical cation and radical anions were estimated from the energies of the individual species. All proton transfers were found to be energetically unfavorable except for the GC anion radical which is favored by 13 kcal. INDO calculations for ions of stacked four base DNA model system AT/GC predictmore » the site of electron trapping in DNA model system is thymine, and the hole is found on guanine as predicted from ab initio energies for the individual bases. Both ab initio and INDO results for the AT/GC anion predict the site of the anion shifts from thymine to cytosine on the transfer of a proton from guanine to the cytosine anion. These results lead to a revised model for ion radical localization after irradiation of DNA. 54 refs., 7 figs., 4 tabs.« less