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Title: Membrane-active peptides
Author: Darkes, Malcolm James Murray
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 1999
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Neurokinin A, (NKA), belongs to the tachykinin family, a group of small amphipathic peptides that bind to specific membrane-embedded G-protein-coupled receptors. The cell membrane acts as a solvent to accumulate peptide and an inducer of peptide secondary structure. The 3-dimensional shape that the peptide assumes when associated to the cell membrane will be an important parameter with regards receptor selectivity and affinity. Receptor affinity appears to depend on the different secondary structures of each tachykinin, which share the same hydrophobic C-terminal sequence, FXGLM. Binding of tachykinins to phospholipid bilayers may take place both on the aqueous membrane surface and in the hydrophobic region. Therefore, neutron diffraction measurements were carried out on highly aligned phospholipid multi-bilayers in order to define the location of the N- and C-terminus of NKA. This study reports that the bilayer location of NKA is remarkably similar to that of substance P, thereby inferring that finer levels of structure must control receptor specificity. Circular dichroism studies were carried out in order to define the conformation of NKA in structure-inducing solvents and in a range of disperse systems. NKA was found to be in a random coil conformation in many of the solvents but exhibited considerable b-sheet conformation in octan-1-o1. These results are related to the neutron diffraction data. A model of the NKA-bilayer interaction is presented using the results from these experiments and from other biophysical techniques. X-ray diffraction measurements shown that the peptide reduces the d-repeat of the membrane prior to the onset of an inverted cubic phase. This suggests that membrane thinning may play a role in peptide-induced model membrane fusion and strengthens the link between the fusion pathway and inverted cubic phase formation. The results of this study are interpreted in relation to models of the membrane fusion mechanism. Also included in this thesis is a study that aims to improve lamellar neutron diffraction data collection and analysis.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available