Author

Ming Ye , '23

Date of Award

Spring 2023

Document Type

Thesis

Terms of Use

© 2023 Ming Ye. This work is freely available courtesy of the author. It may be used under the terms of the Creative Commons Attribution-ShareAlike 4.0 International (CC BY-SA 4.0) license. For all other uses, please contact the copyright holder.

Creative Commons License

Creative Commons Attribution-Share Alike 4.0 International License
This work is licensed under a Creative Commons Attribution-Share Alike 4.0 International License.

Degree Name

Bachelor of Arts

Department

Chemistry & Biochemistry

First Advisor

Liliya A. Yatsunyk

Abstract

DNA can fold into G-quadruplexes (GQs), non-canonical secondary structures formed by stacking of G-tetrads. GQs are important in many biological processes, which makes them promising therapeutic targets for anticancer and antiviral drugs. Therefore, investigating the interaction between GQs and small-molecule ligands is important.

This thesis work surveyed the DNA-ligand interactions of over 20 GQ-ligand complexes via biophysical and X-ray crystallographic methods. Two sets of GQ-ligand complexes were characterized in detail. One set is a group of purine-only sequences, named GA, with a highly selective GQ ligand, N-methyl mesoporphyrin IX (NMM). The other set is a human telomeric sequence, Tel22, with a triangular-shaped aromatic ligand, TrisQ. We utilized circular dichroism, UV-Vis spectroscopy and native PAGE to assess the impact of ligand binding to GQ conformation, stability, and oligomeric states. For GA sequences, the binding stoichiometry and affinity of ligands were also determined via UV-Vis and fluorescence titrations. This work also reports three X-ray crystal structures, two are published (GA1-NMM and GA3-NMM) and one is preliminary (Tel22-TrisQ). In GA1-NMM and GA3-NMM structures, two novel structural features were observed: 1) a ‘symmetry tetrad’ at the dimer interface, which is formed by two guanines from each GQ monomer and 2) a NMM dimer in GA1-NMM. Overall, this work contributes greatly to our understanding of the impact on GQ by ligand binding and modes of interaction of small molecule ligands to GQs, providing structural details that could inform future drug designs.

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