Objective
b-sheet peptides are of potential interest as model systems for understanding pathological disease states such as deposition of amyloid. As with prion related diseases, protein aggregation is responsible for fibril formation through b-sheet interactions and has been linked with Alzheimer's disease, premature senility, scrapie, CJD and BSE. Moreover, molecular recognition phenomena are often fundamentally dependent on large number of weak non-covalent interactions and their co-operative interplay. Co-operativity frequently complicates the analysis because specific changes in structure at one site can affect interactions elsewhere, reflecting some property of the whole set of linked weak interactions. In order to understand the nature of cooperativity and weak interactions in biological molecular recognition processes, we plan to synthesize b-sheet peptides and analyze their degree of structuration by 1H NMR, circular dichroism and tryptophan fluorescence with the following objectives:
(i) investigate the cooperative interactions between the different strands of de novo designed b-sheet peptides;
(ii) develop b-hairpin model systems to determine the contribution to sheet stability of salt bridges;
(iii) examine the degree to which stability is propagated within b-hairpin peptides; and
(iv) construct new b-sheet motifs for future development in the direction of molecular recognition, with the purpose of understanding pathological disease states related to b-sheet formation. These studies are focused on a possible therapy for amyloid-related diseases by exploring peptide-based treatments that involve competitive binding to amyloid proteins and inhibition of protein aggregation.
The applicant and host will both benefit considerably from the proposed training scheme. The project offers a wide range of different techniques allowing the applicant to acquire skills and new methodologies for studying the conformation and folding of petides in solution, including NMR (500 and 600 MHz), CD and fluorescence spectroscopies, and the use of these methods in quantitative analysis of peptide thermodynamics and stability. Skills will also be learnt in peptide design and purification. The applicant will work in a stimulating environment with the current research group engaged in wide ranging aspects of molecular recognition and structural biology, involving collaborations with other scientists across the medicinal and biological sciences on the Nottingham campus. The current facilities are first rate including a new 600 MHz NMR spectrometer, a CD spectropolarimeter including stopped-flow kinetics and computational chemistry facilities. This environment should provide an ideal research training. The applicant brings his skills in protein structure determination by UV-Vis, CD and fluorescence spectroscopies to the Searly group.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques.
- medical and health sciencesbasic medicineneurologydementiaalzheimer
- natural sciencesphysical sciencesthermodynamics
- natural sciencesphysical sciencesopticsspectroscopyemission spectroscopy
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteins
- natural sciencesbiological sciencesmolecular biologystructural biology
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Topic(s)
Data not availableCall for proposal
Data not availableFunding Scheme
RGI - Research grants (individual fellowships)Coordinator
NOTTINGHAM
United Kingdom