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Relationship Between the Kinetics of Thymine Dimer Formation and the Excited State Dynamics of DNA

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2010, Doctor of Philosophy, Ohio State University, Biophysics.

The cyclobutane pyrimidine dimer is the most prevalent mutagenic UV photoproduct in DNA. Of these, the thymine dimer is the most readily formed and assayed, and is therefore a useful model for this photodamage pathway.

Based on insight into the excited-state dynamics and timescale of thymine dimer formation, we have conducted computational studies of thymine dimer formation in various thymine-only model compounds. Experimental evidence has suggested that the fate of a photoexcited thymine-thymine base step is determined by the conformation of the base step at the instant of photoexcitation. We have used a two-parameter heuristic model to reproduce quantum yields of dimer formation in dTpdT in various water:organic co-solvent mixtures. Furthermore, we have showed that specific precursor conformations exist where these two bonds are closely aligned, which we hypothesized will dimerize on an ultrafast timescale upon photoexcitation.

We studied the mean dimer precursor conformation predicted above as well as the canonical B-form conformation using DFT and CIS methods. These results suggest that B-form DNA has primarily localized excited states, and would undergo internal conversion back to the ground state in a manner similar to isolated thymine bases. On the other hand, the mean dimer precursor conformations identified in our heuristic study has a distinct photoreactive excited state, featuring significant weakening of the C5-C6 double bonds as well as putative bonding patterns needed for formation of the cyclobutane ring. We propose that population of this excited state leads to concerted cyclobutane pyrimidine dimer formation as predicted in the literature.

We have further shown that dimer formation can be predicted using CIS calculations for the atom-atom overlap-weighted density matrix elements using the natural bond orbital formalism. These have allowed us to develop semi-heuristic models, where we assume that dimer formation occurs if and only if an increase in the C5-C5 and C6-C6 bond orders is observed upon photoexcitation. This approach has allowed us to predict dimer formation quantum yields that are in line with experiment for dTpdT in various water:co-solvent mixtures as well as with its LNA analog (LNA[TT]) and in a model compound for poly(dT). The results above suggest that dimer formation in thymine-only systems can be predicted directly by considering the dynamics on the excited-state surface. However, we lack systematic data providing a firm basis for considering the sequence dependence of thymine dimer formation, precluding an understanding of the biophysics underlying the observed sequence dependence. We have shown that the sequence dependence of thymine dimer formation is largely a function of the immediate flanking bases about the TT base step. Furthermore, we propose that exciplex formation with flanking purine bases is associated with a decrease in the dimer yield. We also show that dimer photosplitting is significantly sequence dependent, with contributions other than self-repair from a 5’-flanking guanine base to consider.

Dongping Zhong, PhD (Advisor)
Bern Kohler, PhD (Advisor)
Chenglong Li, PhD (Committee Member)
Sherwin Singer, PhD (Committee Member)
339 p.

Recommended Citations

Citations

  • Law, Y. K. (2010). Relationship Between the Kinetics of Thymine Dimer Formation and the Excited State Dynamics of DNA [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1276861431

    APA Style (7th edition)

  • Law, Yu Kay. Relationship Between the Kinetics of Thymine Dimer Formation and the Excited State Dynamics of DNA. 2010. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1276861431.

    MLA Style (8th edition)

  • Law, Yu Kay. "Relationship Between the Kinetics of Thymine Dimer Formation and the Excited State Dynamics of DNA." Doctoral dissertation, Ohio State University, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=osu1276861431

    Chicago Manual of Style (17th edition)