Date of Award

Summer 2009

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Chemistry

First Advisor

Dr. Eric Meggers

Abstract

A project was undertaken to elucidate the properties of the simplified glycol nucleic acid (GNA). GNA is novel in the fact that nucleic acid duplexes composed entirely of GNA show thermal stabilities that are superior to those of analogous DNA or RNA duplexes. Furthermore, GNA has been shown to pair with complementary sequences of RNA, but not with DNA.

The first step towards understanding the thermal stabilities of GNA duplexes is the development of a straightforward synthesis of the phosphoramidites for solid phase oligonucleotide synthesis. Chapter 2 describes work towards a new set of exocyclic amino protection groups which could be removed in less time and under milder conditions than those previously reported. This new scheme results in a vastly improved synthesis of the individual phosphoramidites and allows for quicker access to the subsequent oligonucleotides.

With easy access to GNA oligonucleotides in hand, the next goal was to use spectroscopy to compare the duplex formation properties with that of DNA as outlined in Chapter 3. These studies pointed to the preorganization of the single strands and increased stacking interactions as the main factors that increase the stability of GNA duplexes.

Although the studies in Chapter 3 present a basic understanding of GNA duplex formation, it did not provide the direct structural insight that was desired. Chapter 4 presents the synthesis and pairing properties of three artificial metal-mediated base pairs in GNA duplexes; one of which was used as a handle in an 8-mer duplex for phasing the crystallographic data, thereby providing the initial structural insight that was desired.

Uncertain as to the extent by which the artificial metal-mediated base pair perturbs the overall structure of GNA, several other structures of GNA duplexes containing exclusively Watson-Crick base pairs are presented in Chapter 5. The most impressive structure of a 6-mer GNA duplex displays many common structural features to that of the 8-mer duplex containing artificial base pairs.

Overall this research has provided insight into the exceptional duplex formation properties of glycol nucleic acids and should provide the basis for future research on the application of GNA duplexes for various biological or technical purposes.

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