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Investigating DNA Damage Caused by Reactive Oxygen and Nitrogen Species via Guided-Ion-Beam Scattering and Computational Techniques /

Record Type:	Electronic resources : Monograph/item
Title/Author:	Investigating DNA Damage Caused by Reactive Oxygen and Nitrogen Species via Guided-Ion-Beam Scattering and Computational Techniques // Jonathan Benny.
Author:	Benny, Jonathan,
Description:	1 electronic resource (190 pages)
Notes:	Source: Dissertations Abstracts International, Volume: 86-07, Section: B.
Contained By:	Dissertations Abstracts International86-07B.
Subject:	Chemistry. -
Online resource:	https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=31768551
ISBN:	9798302159687

Investigating DNA Damage Caused by Reactive Oxygen and Nitrogen Species via Guided-Ion-Beam Scattering and Computational Techniques /
Benny, Jonathan,

Investigating DNA Damage Caused by Reactive Oxygen and Nitrogen Species via Guided-Ion-Beam Scattering and Computational Techniques /Jonathan Benny. - 1 electronic resource (190 pages)

Source: Dissertations Abstracts International, Volume: 86-07, Section: B.

Among DNA nucleobases, guanine (G) is the primary target for one-electron ionization and oxidation, generating G●+ through various processes, including photooxidation, electrocatalytic oxidation, DNA-binding transition metals, ionizing radiation, and photolysis. This is due to the low adiabatic ionization potential and oxidation potential of guanine. Electron holes from other nucleobases can move to guanine, proving that G●+ production traps oxidative DNA damage. G●+ formation can exacerbate DNA damages and cause secondary reactions from reactive oxygen species (ROS) and reactive nitrogen species (RNS) during pathological processes. The following three projects were conducted using a customized electrospray ionization (ESI) guided-ion-beam tandem mass spectrometer, reaction potential energy surface calculations, and kinetics modeling.In project 1, the interaction of the lowest excited singlet molecular oxygen (1O2) with radical cations of 8-bromoguanine (8BrG●+) and 8-bromoguanosine (8BrGuo●+) was investigated using a custom-built ESI guided-ion beam scattering tandem mass spectrometer in the gas phase. This study seeks to explore the synergistic, oxidatively induced damage of 8-brominated guanine and guanosine that could arise from ionizing radiation, one-electron oxidation, and 1O2 oxidation. Utilizing measurements of reaction product ions and cross sections of 8BrG●+ and 8BrGuo●+ with 1O2 through guided-ion beam tandem mass spectrometry, complemented by computational modeling of the prototype reaction system, 8BrG●+ + 1O2, employing the approximately spin-projected ωB97XD/6-31+G(d,p) density functional theory, the coupled cluster DLPNO-CCSD(T)/aug-cc-pVTZ, and the multireference CASPT2(21,15)/6-31G**, the probable reaction products and potential energy surfaces (PESs) were systematically mapped out. The oxidation products of 8BrG●+ and 8BrGuo●+ are comparable in terms of exothermicity, and their reaction efficiencies with 1O2 increase as collision energy decreases. Both single- and multireference theories indicated that the two most energetically favorable reaction pathways correspond to 1O2-addition at the C8 and C5-positions of 8BrG●+, respectively. The CASPT2-calculated PES demonstrates a strong quantitative alignment with the experimental benchmark, as the oxidation exothermicity closely matches the water hydration energy of the product ions, thereby facilitating the elimination of a water ligand in the product ions.In project 2, the reaction dynamics between nitric oxide (●NO) and the radical cations of guanine (9HG●+) and 9-methylguanine (9MG●+) were investigated. Nitric oxide (●NO) is involved in various biological processes, including the enhancement of DNA radiosensitivity in radiotherapy that utilizes ionizing radiation. The formation of 9HG●+ and 9MG●+ in the gas phase, along with their interactions with ●NO in a guided-ion beam mass spectrometer, facilitated an examination of the charge-transfer and nitrosation reactions involving these radical cations. An intriguing aspect of these processes is the participation of multiple spin configurations in the reaction, including open-shell singlet 1,OS[G●+(↑)⋯(↓)●NO], closed-shell singlet 1,CS[G(↑↓)⋯NO+], and triplet 3[G●+(↑)⋯(↑)●NO].First, the kinetic energy-dependent product ion cross sections for both charge-transfer reactions indicated a threshold energy of 0.24 (or 0.37) eV above the 0 K product 9HG (or 9MG) + NO+ asymptote. The findings indicated that the charge transfer reaction necessitates the engagement of a triplet-state surface derived from a reactant-like precursor complex 3[9MG●+(↑)⋅(↑)●NO] with a closed-shell singlet-state surface progressing from a charge-transferred complex 1[9MG⋅NO+]. In the reaction, an electron is transported from π∗(NO) to the perpendicular π∗(9MG), resulting in a modification in orbital angular momentum. The former compensates for the alteration in electron spin angular momentum and enables intersystem crossing. The reaction threshold exceeding 0 K thermochemistry and the low charge-transfer efficiency are explained by the vibrational excitation in the resultant ion NO+ and the kinetic shift resulting from a long-lived triplet intermediate.Second, the nitrosation reactions of ●NO with both unsubstituted guanine radical cations (in the 9HG●+ conformation) and 9-methylguanine radical cations (9MG●+, a guanosine-mimicking model molecule) were examined in both the absence and presence of monohydration of radical cations. The measurement of reaction product ions and cross sections dependent on kinetic energy was conducted utilizing an electrospray ionization guided-ion beam tandem mass spectrometer. The reaction mechanisms, kinetics, and dynamics were understood through the analysis of the reaction potential energy surface utilizing spin-projected density functional theory, coupled cluster theory, and multiconfiguration complete active space second-order perturbation theory, succeeded by RRKM kinetics modeling. The experimental and computational results indicated that closed-shell singlet 1,CS[7- NO-9MG]+ is the predominant exothermic product, while triplet 3[8-NO-9MG]+ is the lesser, endothermic product. Singlet biradical products were undetectable owing to significant reaction endothermicities, activation barriers, and intrinsic instability.In project 3, the examination has broadened to include the oxidatively-damaged 8-oxoguanine (OG), a common DNA lesion resulting from oxidative stress caused by ionizing radiation, reactive oxygen species, chemical oxidation, photooxidation, and several other factors present in cells and tissues. A study was conducted to investigate the reaction dynamics of ●NO with 9-methyl-oxoguanine (9MOG●+) radical cations in order to comprehend the radiosensitization effects of ●NO on oxidatively-stressed DNA. The formation of 9MOG●+ in the gas phase and the interactions of the radical cations with ●NO were investigated using a guided-ion beam mass spectrometer, where product ions and cross sections were measured as a function of the center-of-mass collision energy. Reaction potential energy surfaces were computed using different theoretical levels (ωB97XD/6-31+G(d,p), DLPNO-CCSD(T)/aug-cc-pVTZ, and CASPT2/ANO-L-VTZP) and juxtaposed with experimentally determined reaction thermodynamics. In collisions, both open-shell singlet 1,OS[9MOG●+(↑)⋯(↓)●NO] and triplet 3[9MOG●+(↑)⋯(↑)●NO] precursors were generated in a ratio of 1:3. The 1[9MOG●+(↑)⋯(↓)●NO] precursor results in the formation of the primary, exothermic product ion 1,CS[5-NO-9MOG]+, occurring without any activation barriers exceeding those of the reactants. The closed-shell 1,CS[9MOG(↑↓)⋯NO+] state produces the charge transfer products exclusively, as no open-shell or triplet CT product was observable.

English

ISBN: 9798302159687Subjects--Topical Terms:

516420
Chemistry.
Subjects--Index Terms:

DNA

Investigating DNA Damage Caused by Reactive Oxygen and Nitrogen Species via Guided-Ion-Beam Scattering and Computational Techniques /
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520 $a Among DNA nucleobases, guanine (G) is the primary target for one-electron ionization and oxidation, generating G●+ through various processes, including photooxidation, electrocatalytic oxidation, DNA-binding transition metals, ionizing radiation, and photolysis. This is due to the low adiabatic ionization potential and oxidation potential of guanine. Electron holes from other nucleobases can move to guanine, proving that G●+ production traps oxidative DNA damage. G●+ formation can exacerbate DNA damages and cause secondary reactions from reactive oxygen species (ROS) and reactive nitrogen species (RNS) during pathological processes. The following three projects were conducted using a customized electrospray ionization (ESI) guided-ion-beam tandem mass spectrometer, reaction potential energy surface calculations, and kinetics modeling.In project 1, the interaction of the lowest excited singlet molecular oxygen (1O2) with radical cations of 8-bromoguanine (8BrG●+) and 8-bromoguanosine (8BrGuo●+) was investigated using a custom-built ESI guided-ion beam scattering tandem mass spectrometer in the gas phase. This study seeks to explore the synergistic, oxidatively induced damage of 8-brominated guanine and guanosine that could arise from ionizing radiation, one-electron oxidation, and 1O2 oxidation. Utilizing measurements of reaction product ions and cross sections of 8BrG●+ and 8BrGuo●+ with 1O2 through guided-ion beam tandem mass spectrometry, complemented by computational modeling of the prototype reaction system, 8BrG●+ + 1O2, employing the approximately spin-projected ωB97XD/6-31+G(d,p) density functional theory, the coupled cluster DLPNO-CCSD(T)/aug-cc-pVTZ, and the multireference CASPT2(21,15)/6-31G**, the probable reaction products and potential energy surfaces (PESs) were systematically mapped out. The oxidation products of 8BrG●+ and 8BrGuo●+ are comparable in terms of exothermicity, and their reaction efficiencies with 1O2 increase as collision energy decreases. Both single- and multireference theories indicated that the two most energetically favorable reaction pathways correspond to 1O2-addition at the C8 and C5-positions of 8BrG●+, respectively. The CASPT2-calculated PES demonstrates a strong quantitative alignment with the experimental benchmark, as the oxidation exothermicity closely matches the water hydration energy of the product ions, thereby facilitating the elimination of a water ligand in the product ions.In project 2, the reaction dynamics between nitric oxide (●NO) and the radical cations of guanine (9HG●+) and 9-methylguanine (9MG●+) were investigated. Nitric oxide (●NO) is involved in various biological processes, including the enhancement of DNA radiosensitivity in radiotherapy that utilizes ionizing radiation. The formation of 9HG●+ and 9MG●+ in the gas phase, along with their interactions with ●NO in a guided-ion beam mass spectrometer, facilitated an examination of the charge-transfer and nitrosation reactions involving these radical cations. An intriguing aspect of these processes is the participation of multiple spin configurations in the reaction, including open-shell singlet 1,OS[G●+(↑)⋯(↓)●NO], closed-shell singlet 1,CS[G(↑↓)⋯NO+], and triplet 3[G●+(↑)⋯(↑)●NO].First, the kinetic energy-dependent product ion cross sections for both charge-transfer reactions indicated a threshold energy of 0.24 (or 0.37) eV above the 0 K product 9HG (or 9MG) + NO+ asymptote. The findings indicated that the charge transfer reaction necessitates the engagement of a triplet-state surface derived from a reactant-like precursor complex 3[9MG●+(↑)⋅(↑)●NO] with a closed-shell singlet-state surface progressing from a charge-transferred complex 1[9MG⋅NO+]. In the reaction, an electron is transported from π∗(NO) to the perpendicular π∗(9MG), resulting in a modification in orbital angular momentum. The former compensates for the alteration in electron spin angular momentum and enables intersystem crossing. The reaction threshold exceeding 0 K thermochemistry and the low charge-transfer efficiency are explained by the vibrational excitation in the resultant ion NO+ and the kinetic shift resulting from a long-lived triplet intermediate.Second, the nitrosation reactions of ●NO with both unsubstituted guanine radical cations (in the 9HG●+ conformation) and 9-methylguanine radical cations (9MG●+, a guanosine-mimicking model molecule) were examined in both the absence and presence of monohydration of radical cations. The measurement of reaction product ions and cross sections dependent on kinetic energy was conducted utilizing an electrospray ionization guided-ion beam tandem mass spectrometer. The reaction mechanisms, kinetics, and dynamics were understood through the analysis of the reaction potential energy surface utilizing spin-projected density functional theory, coupled cluster theory, and multiconfiguration complete active space second-order perturbation theory, succeeded by RRKM kinetics modeling. The experimental and computational results indicated that closed-shell singlet 1,CS[7- NO-9MG]+ is the predominant exothermic product, while triplet 3[8-NO-9MG]+ is the lesser, endothermic product. Singlet biradical products were undetectable owing to significant reaction endothermicities, activation barriers, and intrinsic instability.In project 3, the examination has broadened to include the oxidatively-damaged 8-oxoguanine (OG), a common DNA lesion resulting from oxidative stress caused by ionizing radiation, reactive oxygen species, chemical oxidation, photooxidation, and several other factors present in cells and tissues. A study was conducted to investigate the reaction dynamics of ●NO with 9-methyl-oxoguanine (9MOG●+) radical cations in order to comprehend the radiosensitization effects of ●NO on oxidatively-stressed DNA. The formation of 9MOG●+ in the gas phase and the interactions of the radical cations with ●NO were investigated using a guided-ion beam mass spectrometer, where product ions and cross sections were measured as a function of the center-of-mass collision energy. Reaction potential energy surfaces were computed using different theoretical levels (ωB97XD/6-31+G(d,p), DLPNO-CCSD(T)/aug-cc-pVTZ, and CASPT2/ANO-L-VTZP) and juxtaposed with experimentally determined reaction thermodynamics. In collisions, both open-shell singlet 1,OS[9MOG●+(↑)⋯(↓)●NO] and triplet 3[9MOG●+(↑)⋯(↑)●NO] precursors were generated in a ratio of 1:3. The 1[9MOG●+(↑)⋯(↓)●NO] precursor results in the formation of the primary, exothermic product ion 1,CS[5-NO-9MOG]+, occurring without any activation barriers exceeding those of the reactants. The closed-shell 1,CS[9MOG(↑↓)⋯NO+] state produces the charge transfer products exclusively, as no open-shell or triplet CT product was observable.
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