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Modeling DNA Damage
Stockholm University, Faculty of Science, Department of Physical, Inorganic and Structural Chemistry.
Responsible organisation
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

In this thesis methods of computational chemistry have been used to examine DNA damaging processes initiated by ionizing radiation, free radicals, or Low-Energy Electrons (LEE).

The computational chemistry method based on quantum mechanics that has been mainly used here is the Density Functional Theory (DFT). The Car-Parrinello Molecular Dynamics (CPMD) method, which includes the dynamics of atoms, has also been used. For enabling calculations of large systems the hybrid Quantum Mechanics/Molecular Mechanics (QM/MM) method has been applied by treating the chemically relevant part with quantum mechanics and the rest of the system with molecular mechanics.

Herein, several types of DNA damaging processes have been examined by performing calculations on models of sections of DNA. A detailed description of how DNA becomes damaged is of major importance for understanding and treating diseases such as cancer.

Hydrogen abstractions by nucleobase radicals have been investigated as an initial step leading to DNA strand break or base release. The nucleobase radicals that have been examined are uracil-5-yl, uracil-5-peroxyl, and hydroxyl-thymine. The uracil-5-yl radical was identified as the prominent hydrogen abstracting radical.

Secondary electrons with low energy, LEEs, produced in the tracks of ionizing radiation can reduce nucleotides in DNA and thereby create an unstable anion nucleotide radical. The aim of these studies has been to investigate the effect of LEE attachment on cytosine and guanine nucleotides in an aqueous environment. To verify the possibility of strand break in DNA the ruptures of the phosphodiester bonds, which link the deoxyriboses and the phosphate groups, were analyzed. This study revealed that strand break most likely would occur when a guanine nucleotide, compared with other nucleotides, becomes reduced by an LEE in an aqueous environment.

Place, publisher, year, edition, pages
Stockholm: Institutionen för fysikalisk kemi, oorganisk kemi och strukturkemi , 2008. , 83 p.
Keyword [en]
DNA, Ionizing radiation, DNA radicals, Strand break, Hydrogen abstraction, Density Functional Theory, Car-Parrinello Molecular Dynamics, QM/MM
National Category
Physical Chemistry
Research subject
Physical Chemistry
Identifiers
URN: urn:nbn:se:su:diva-8246ISBN: 978-91-7155-756-8 (print)OAI: oai:DiVA.org:su-8246DiVA: diva2:199896
Public defence
2008-10-30, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 12 A, Stockholm, 10:00 (English)
Opponent
Supervisors
Available from: 2008-10-09 Created: 2008-10-02 Last updated: 2010-01-27Bibliographically approved
List of papers
1. Hydrogen abstraction from deoxyribose by a neighbouring uracil-5-yl radical
Open this publication in new window or tab >>Hydrogen abstraction from deoxyribose by a neighbouring uracil-5-yl radical
2007 In: Physical Chemistry Chemical Physics, ISSN 1463-9076, Vol. 9, no 45, 5975- p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:su:diva-25521 (URN)000250931600003 ()
Note
Part of urn:nbn:se:su:diva-8246Available from: 2008-10-09 Created: 2008-10-02Bibliographically approved
2. Hydrogen Abstraction from Deoxyribose by a Neighboring 3 '-Uracil Peroxyl Radical
Open this publication in new window or tab >>Hydrogen Abstraction from Deoxyribose by a Neighboring 3 '-Uracil Peroxyl Radical
2009 (English)In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 113, no 18, 6574-6578 p.Article in journal (Refereed) Published
Abstract [en]

Theoretical examination of the reactivity of the uracil-5-peroxyl radical when abstracting a hydrogen atom from a neighboring 5'-deoxyribose in 5'-ApU-5-peroxyl-3' has been performed using density functional theory with the MPWB1K functional. Halogenated uracils are often used as radiosensitizers in DNA since the reactive uracil-5-yl radical is formed upon radiation and is known to create strand break and alkali-labile sites. Under aerobic conditions, such as in the cell, it has been proposed that the uracil-5-peroxyl radical is formed and would be the damaging agent. Our results show low reactivity for the uracil-5-peroxyl radical, determined by calculating the activation and reaction energies for the plausible hydrogen abstraction sites C1', C2' and C3' of the neighboring 5'-deoxyribose. These findings support the hypothesis that hydrogen abstraction primarily occurs by the uracil-5-yl radical, also under aerobic conditions, prior to formation of the peroxyl radical.

Keyword
DENSITY-FUNCTIONAL THERMOCHEMISTRY; SEQUENCE-SELECTIVE PHOTOREACTION; UV-IRRADIATION; EXACT-EXCHANGE; DUPLEX DNA; MODELS; OLIGONUCLEOTIDES; 5-HALOURACILS; DAMAGE
Identifiers
urn:nbn:se:su:diva-35595 (URN)10.1021/jp9007569 (DOI)000265687500047 ()
Available from: 2010-01-22 Created: 2010-01-19 Last updated: 2017-12-12Bibliographically approved
3. Hydroxyl radical – thymine adduct induced DNA damages
Open this publication in new window or tab >>Hydroxyl radical – thymine adduct induced DNA damages
2008 In: Chemical Physics Letters, ISSN 0009-2614, Vol. 458, no 1-3, 186-189 p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:su:diva-25523 (URN)000256284900039 ()
Note
Part of urn:nbn:se:su:diva-8246Available from: 2008-10-09 Created: 2008-10-02Bibliographically approved
4. Phosphodiester bond rupture in 5' and 3' cytosine monophosphate in aqueous environment and the effect of low-energy electron attachment: A Car-Parrinello QM/MM molecular dynamics study
Open this publication in new window or tab >>Phosphodiester bond rupture in 5' and 3' cytosine monophosphate in aqueous environment and the effect of low-energy electron attachment: A Car-Parrinello QM/MM molecular dynamics study
2008 In: Chemical Physics Letters, ISSN 0009-2614, Vol. 462, no 4-6, 289-294 p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:su:diva-25524 (URN)000258830900031 ()
Note
Part of urn:nbn:se:su:diva-8246Available from: 2008-10-09 Created: 2008-10-02Bibliographically approved
5. On the effect of low-energy electron induced DNA strand break in aqueous solution: A theoretical study indicating guanine being a weak link in DNA
Open this publication in new window or tab >>On the effect of low-energy electron induced DNA strand break in aqueous solution: A theoretical study indicating guanine being a weak link in DNA
2008 In: Journal of the American Chemical Society, ISSN 0002-7863, Vol. 130, no 37, 12254-12255 p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:su:diva-25525 (URN)000259139900027 ()
Note
Part of urn:nbn:se:su:diva-8246Available from: 2008-10-09 Created: 2008-10-02Bibliographically approved

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