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Title: Conformational switching for transmembrane communication
Author: Brown, Robert A.
Awarding Body: University of Manchester
Current Institution: University of Manchester
Date of Award: 2013
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G-Protein coupled receptors function by communicating the conformational changes induced during binding to an extracellular ligand through the phospholipid bilayer to the cell interior. Previous work has shown that synthetic oligomers of Aib (2-aminoisobutyric acid) can communicate stereochemical information over similar distances through thermodynamic control of their helical screw-sense preference. This thesis details the development of new membrane-compatible methods to control and detect conformational preferences in Aib oligomers, to allow the future construction of a synthetic GPCR mimic capable of signal transduction through an artificial vesicle membrane. A 13C-labelled NMR probe was synthesised and exploited to unequivocally determine that chiral tertiary and quaternary L-amino acid residues induce opposing screw-sense preferences from the N-terminus of the helix. The synthesis and characterisation of new N-terminal screw-sense controllers based on iminoboronate and cyclo-aminoboronate complexes is discussed. It was also shown that a synthetic N-terminal binding site constructed from an aminoboronate motif facilitates the switchable biomimetic input of stereochemical information from chiral vicinal diol or ribonucleoside ligands. Finally, the synthesis of new C-terminal bis-pyrene conformational reporters, and their successful fluorimetric detection of remotely induced screw-sense preferences are described.
Supervisor: Webb, Simon; Clayden, Jonathan Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available