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Structural Characteristics of the DNA i-Motif and its Interactions with Small Molecules

  • Author(s): Commendatore, Eric James
  • Advisor(s): Morton, Thomas H
  • Figadère, Bruno
  • et al.
Creative Commons Attribution 4.0 International Public License
Abstract

Single-stranded secondary structures have been of increasing importance. Until this past year, the study of the i-motif was far less investigated compared to the G-quadruplex. However, the discovery of in vivo i-motif formations in telomeric DNA has resurged investigations.

The premier chapter of this dissertation, provides a background of the i-motif. The hierarchy of hemi-protonated dimers, constraints of loop length, importance of ionic environment, steric media, and pH all play significant roles in the formation and stabilization of the i-motif. Finally, a brief introduction to the biophysical techniques presented in this manuscript is provided.

The second chapter concerns an array of small molecule interactions encompassing hydrogen bonding, intercalation, and phosphate interactions. The Morton laboratory has created novel compounds to interact with this structure. Each compound was halted in its study for different reasons, but the ground work provided allowed for future explorations.

The penultimate chapter delves into the structure elucidation for the c-MYC coding region which creates the i-motif. As of this writing, the interactions of coding regions have not been explored. Due to the importance of superhelicity and the direct disruption of transcription, the coding region of such a prominent oncogene is of interest. Using mostly NOESY and TOCSY NMR experiments the structure of this i-motif can be gathered. It is important to note the structure does not provide the same level of detail that is often found within structural literature. However, the DNA bases in the unstructured loops, the hemi-protonated dimers of the core, and isomerization of the i-motif structure can be garnered.

The final chapter utilizes the structural and biophysical information that has been explored and details the interaction of aplysinopsins with the DNA i-motif. In this exploration, it was found that the E and Z isomers of these products interact differently with the DNA i-motif. The interaction of the E isomer was tighter overall, but the interaction of the Z isomer seemed to bind in a specific way to the i-motif. An induced chirality, fluorescence increases/quenching, 31P NMR, and multi-dimensional NMR all point to an interaction with the i-motif that is trackable and can be manipulated.

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