Date of Award

Spring 2020

Document Type

Thesis

Terms of Use

© 2020 Linda Yingqi Lin. All rights reserved. This work is freely available courtesy of the author. It may only be used for non-commercial, educational, and research purposes. For all other uses, including reproduction and distribution, please contact the copyright holder.

Degree Name

Bachelor of Arts

Department

Chemistry & Biochemistry Department

First Advisor

Liliya A. Yatsunyk

Abstract

Non-canonical DNA structures known as G-quadruplexes (GQs) and i-motifs can form from G-rich and C-rich sequences within the genome, respectively, which are prominent within telomeres and oncogene promoters. These non-canonical quadruplexes likely play roles in regulating gene expression and in DNA replication and repair. However, much remains to be understood about their structural features and diversity. In this work, we investigate the interaction of a GQ-forming sequence with a water-soluble porphyrin, N-methyl mesoporphyrin IX (NMM). Biophysical studies revealed an impressively tight, thermodynamically favorable binding interaction. We then solved the GQ-NMM crystal structure at 2.39 Å, which showed that the DNA forms a dimer of parallel GQs with NMM bound at both ends via end-stacking interactions. Furthermore, we demonstrate that an unusually large, four-tetrad GQ adopts the same structure in solution as it does in crystalline form, thereby validating the crystal structure. We characterize its loop mutants to show that loop interactions fine tune GQ stability, but do not affect GQ folding. Finally, we present ongoing work towards solving the crystal structures of a different GQ-ligand complex and of a monomolecular i-motif. The work in this thesis advances our understanding of quadruplex structural diversity and ligand binding interactions by contributing to the limited number of solved GQ-ligand crystal structures, as well as by characterizing an atypically large GQ. Non-canonical quadruplexes likely function in vivo as regulatory elements. Accordingly, our improved understanding of their structural features informs the design and in silico screening of novel drugs, which can selectively recognize these features and subsequently modulate quadruplex stability for therapeutic purposes, particularly against cancer.

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