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DFT modeling of DNA phosphate adducts from alkyl epoxides and consequent strand break
Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry. Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
2019 (English)Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
Abstract [en]

Predictive toxicology with methodologies that are ethical with regard to animal testing is increasingly important in our world, where new chemicals are constantly being produced and to an extent let out into the environment for which risk assessments needs to be performed. Could in silico, toxicology by computation, methods aid in this? The monoepoxides, glycidamide and butadiene monoxide, are CYP450 metabolites of acrylamide and 1,3-butadiene, respectively. They may form adducts to DNA at different sites, amongst them the phosphate at the DNA backbone. The adduct formation may lead to mutations, including a consequent single strand break of the DNA. This break is proposed to occur due to rearrangement into a stable five ring. In this study, a computational model system for the adduct formation and consequent strand break was developed in order to determine if adducts and single stranded break products are thermodynamically favorable, hence spontaneous, to occur. The computational method used was density functional theory at B3LYP level of theory with a range of basis sets, 6-31G(d), 6-311G(d), cc-pVDZ and cc-pVTZ. This computational method was to some extent compared with a semi-empirical method using PM6 level of theory. With the developed model, adduct formation was shown to occur for both glycidamide and butadiene monoxide, but the single stranded break was not proven to be thermodynamically favorable. Further modelling work could include doing the reaction with a water solvation model and sodium ions as counter ions. Optimizing the DNA model to predict strand-break could aid in future assessment of potential genotoxic compounds.

Place, publisher, year, edition, pages
2019. , p. 74
Keywords [en]
DNA, adducts, epoxides, strand-break, DFT (density functional theory), B3LYP, predictive toxicology
National Category
Chemical Sciences Environmental Sciences
Identifiers
URN: urn:nbn:se:su:diva-165819OAI: oai:DiVA.org:su-165819DiVA, id: diva2:1371037
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Available from: 2019-12-09 Created: 2019-11-19 Last updated: 2019-12-09Bibliographically approved

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CiteExportLink to record
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Citation style
  • apa
  • ieee
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