Development of polypyridine metal-dependent switches as artificial regulation sites

Oheix, Emmanuel (2014). Development of polypyridine metal-dependent switches as artificial regulation sites. University of Birmingham. Ph.D.

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Abstract

This thesis describes the design, preparation and study of synthetic peptides dimerised with polypyridine linkers. Their conformational transitions, which result from the coordination of metal-ions, are proposed to trigger the orientation of their peptide substituents, thus allowing for the design of conjugates incorporating artificial regulation sites. To test this hypothesis, different polypyridine linkers were designed, such that the substituents orientation is either dependent or independent of the polypyridine conformations. The approach developed herein includes a detailed conformational study of low-molecular weight species (model conjugates) and the preparation of conjugates mimicking a natural protein, for which dimerisation is essential for its bioactivity. For the latter conjugates, which are based on the GCN4 transcription factor, the influence of metal addition on sequence-specific DNA binding was tested using a combination of spectroscopic and electrophoretic techniques. The results presented herein indicate that metal addition can influence the interaction of the polypyridine peptide conjugates with DNA, depending on the peptides and linkers design, and that this can be partly attributed to a conformational transition of the polypyridine linker. As an extension, the potential of these conjugates as sequence-specific DNA sensors or nuclease agents was partly investigated.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

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