Mutagenicity of 5-bromouracil : quantum chemical study

Uracil--Derivatives;Mutagenicity testing--Mathematical models;Quantum chemistry;Hartree-Fock approximation;Density functionals;Molecular dynamics;Mutagens

Holroyd, Leo ; van Mourik, Tanja ; van Mourik, Tanja

University:University of St Andrews

Department:Chemistry (School of)

关键词: Uracil--Derivatives;    Mutagenicity testing--Mathematical models;    Quantum chemistry;    Hartree-Fock approximation;    Density functionals;    Molecular dynamics;    Mutagens;   

Others  :  https://research-repository.st-andrews.ac.uk/bitstream/handle/10023/7063/LeoHolroydPhDThesis.pdf?sequence=3&isAllowed=y

来源: DR-NTU

【 摘 要 】

This thesis describes a computational investigation of the mutagenicity of 5-bromouracil (BrU).In Chapter 1, three models of spontaneous and BrU-induced base mispairing (rare tautomer, wobble pair, and ion) are reviewed.Chapter 2 presents the computational techniques used: electronic structure methods (Hartree–Fock-based and density functional theory) and molecular dynamics.Chapter 3 presents optimisations of the keto and enol tautomers of BrU and uracil (U) in water clusters.The enol tautomer of BrU is found to be more stable than that of U.Chapter 4 is a molecular dynamics study of the keto-enol tautomerism of BrU and U in a periodic water box.The pKₐ of BrU at N3 is found to be lower than that of U.Chapter 5 is a study of stacked base dimers containing BrU, U, or thymine (T) stacking with natural bases.Some structures were taken from the Protein Data Bank, while others were generated using an in-house methodology.BrU is found to stack more strongly than T in vacuo, but solvation and thermal effects nullify this difference.Chapter 6 discusses the significance of the results in Chapters 3–5 in terms of BrU-induced mutagenesis.Appendices A and B–D provide supplementary material to Chapters 2 and 5, respectively.Appendix E is an investigation of the “base flipping” pathway of 2-aminopurine (2AP).Both 2AP/N and A/N dinucleosides (N = thymine or guanine) are found to adopt a wide range of energy-minimum conformations – not only stacked and “flipped”, but also intermediate – and the stacked are not the most favourable by free energy.Appendix F is a list of publications and papers in preparation.One publication concerns BrU stacking.The other is a conformational study of the dipeptide tyrosine-glycine: the theoretical results are shown to be consistent with experiment (R2PI spectra) if thermal effects are taken into account.