Biophysical study of G-quadruplex structures in solution and G-wire superamolecular assembly on graphene

Guanine-rich nucleic acid sequences have a high propensity to adopt non-B DNA secondary structures like G-quadruplexes. Sequences that could potentially form G-quadruplexes are widespread throughout the genome and found to be more prominent in biologically critical regions. They may play biological significant roles in telomere maintenance, as well as regulation of gene transcription, replication and recombination. G-quadruplex DNA is highly polymorphic. The study of G-quadruplex structures has attracted intense interests in the field of potential therapeutic targeting in human cancers. Structural uniqueness of G-quadruplex DNA can serve as specific recognition site for G-quadruplex interactive compounds. In Chapter 3, the structure of four-repeat Giardia telomeric sequence d[TAGGG(TAGGG)3], which differs from the human counterpart d[TAGGG(TTAGGG)3] only by one T deletion within the non-G linker in each repeat, was solved by NMR to explore the effect of loop length and sequence on the folding topology of G-quadruplexes. Two different intramolecular G-quadruplexes were found to coexist and interconvert in K+ solution. Recurrence of several structural elements in the observed structures suggests a “cut and paste” principle for the design and prediction of G-quadruplex topologies, for which different elements could be extracted from one G-quadruplex and inserted into another. The unique properties of G-quadruplex DNA compared to duplex DNA make them amenable for development of nanomaterials. In Chapter 4, Self-assembly of supramolecular G-wires, grown from the oligonucleotide d(GGGGTTGGGG), on graphene sheets were investigated. Atomic force microscope (AFM) and micro-Raman mappin results demonstrate for the first time that G-wires are well-ordered and preferentially oriented along the armchair direction of graphene. Such assembly could be further exploited for the development of graphene-based molecular device and biosensor. It can be envisioned that the development of the understanding of the thermodynamic properties and structural features of G-quadruplex DNA will endow new capabilities for structural nucleic acid nanotechnology.DOCTOR OF PHILOSOPHY (SPMS