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Type of Document Dissertation Author Tran, Pierre Author's Email Address ptran@nd.edu URN etd-06232004-100645 Title Computational Investigations of Thymidine Dimer Incorporated into a Double Strand DNA and Synthesis of a CPD Building Block and a Single Strand of DNA Containing a CPD Degree Doctor of Philosophy Department Chemistry and Biochemistry Advisory Committee
Advisor Name Title Bei Hu Committee Chair Dan Gezelter Committee Member Marvin J. Miller Committee Member Olaf G. Wiest Committee Member Paul Huber Committee Member Keywords
- DNA building block synthesis
- amber forcefield
- molecular dynamic simulations
- cyclobutane pyrimidine dimer
- skin cancer
- photodamaged DNA
Date of Defense 2004-05-18 Availability unrestricted Abstract Cis-syn cyclobutane pyrimidine dimer and the (6-4) photoproduct are the main photo lesions formed following UV irradiation of skin cells. These lesions are responsible for cell death and development of skin cancers. Consequently, all organisms have developed DNA repair mechanisms to preserve the integrity of the genetic material. Crystallography, nuclear magnetic resonance, and spectroscopic analyses have shown that many enzymes “flip” the damaged base pairs out of the DNA duplex for repair. However, this process is poorly understood.The main problem with photodamaged DNA is the “flipped-out” structure, which cannot be resolved by any existing analytical method because of its small concentration. Additionally, the postulated “flipping” mechanism, now widely accepted and sometimes observed for other repair phenomenon, is a very fast process. The CPD in the “flipped out” form is also not the most thermodynamically favorable product; its concentration is not measurable by present analytical methods.
Our first goal is to simulate the structure dynamics of the DNA in the presence of the CPD using AMBER program and to investigate the general perturbation of the conformations of base pairs surrounding the photo-lesion product. A comparative analysis of the “flipped-in” and the “flipped out” structures allowed us to understand the local deformations of the DNA structure in the presence of the CPD.
In a second part, to address questions regarding a possible dependence of the DNA sequence on the recognition of the photodamaged units by the artificial enzymes, several examples of modified DNA strands have been studied. Four adjacent base pairs to the lesion have been modified, and the study of the impact of these modifications has been used in comparison with the data found in the first part.
Finally, in preparation for experimental testing of artificial enzyme units on the double stranded DNA, a synthesis of the CPD unit as well as the synthesis of a single strand DNA with the CPD incorporated has been accomplished. These key compounds are used later as prototype in the design of artificial photolyases.
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