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FLuoroAromatic-Thiol Tags (FLA-SH Tags) as probes to understand protein folding, interactions and dynamics

School of Engineering & Physical Sciences

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Dr C Coxon No more applications being accepted Funded PhD Project (European/UK Students Only)

About the Project

This project will explore the design, synthesis and optimisation of a new class of biocompatible cysteine-selective fluorinated probes to study protein conformation, dynamics, interactions, (mis-/un) folding and aggregation in real-time at the single molecule level using 19F NMR. This research will help to improve our understanding of why proteins fold and why this can go wrong in disease.

Proteins and peptides can adopt dynamic 3D folded structures that perform specific functions in biology. In some cases, proteins can fold incorrectly, which at best leaves them non-functional, or at worst, pathogenic. Protein misfolding is implicated in a number of mainly neurological/neurodegenerative diseases e.g. Parkinson’s disease, yet the exact structural and biological causes of protein-folding are poorly understood and new tools are required to study this phenomenon at the molecular level.

Fluorinated proteins and peptides provide valuable tools to study peptide behaviour e.g. regional and global information about the protein conformation using 19F NMR, mainly due to the high-sensitivity, uncomplicated spectral data produced and low background signal (Verhoork, Biochem. 2019, 57, 43, 6132-6143). However, fluorinated amino acids can be challenging to incorporate into whole protein systems. The Coxon Lab has experience in studying probes that can specifically react with certain amino acid side chains (Verhoork Chem. Eur. J. 2019, 25, 177; Giminez, Org. Biomol. Chem. 2017, 15, 4086; Giminez, Org. Biomol. Chem. 2017, 15, 4081), yet these typically require organic solvents or non-bio-friendly conditions and are not applicable to proteins in native environments.
This project will explore the design, synthesis and optimisation of a new class of biocompatible cysteine-selective fluorinated probes. These will then be applied to study model protein conformation, dynamics, interactions, (mis-/un-)folding and aggregation in real-time at the single molecule level using 19F NMR. The aim is to extend this to proteins related to neurodegeneration to better understand the structural, environmental and biological reasons for their misfolding. You will be provided with training in solid phase peptide synthesis, mass spectrometry, high-field NMR, as well as protein expression and purification techniques.

Name of supervisor: Dr Chris Coxon, email: [Email Address Removed]

All applicants must have or expect to have a 1st class MChem, MPhys, MSci, MEng or equivalent degree by Autumn 2020. Selection will be based on academic excellence and research potential, and all short-listed applicants will be interviewed (in person or by Skype). Some of our scholarships are only open to UK/EU applicants who meet residency requirements set out by EPSRC. Some scholarships are available for exceptional overseas candidates

Closing Date
All applications must be received by 28th February 2020. All successful candidates should usually expect to start in September/October 2020.

How to Apply
Apply Online:
When applying through the Heriot-Watt on-line system please ensure you provide the following information:
(a) in ‘Study Option’
You will need to select ‘Edinburgh’ and ‘Postgraduate Research’. ‘Programme’ presents you with a drop-down menu. Choose Chemistry PhD and select September 2020 for study option (this can be updated at a later date if required)
(b) in ‘Research Project Information’
You will be provided with a free text box for details of your research project. Enter Title and Reference number of the project for which you are applying and also enter the supervisor’s name.

This information will greatly assist us in tracking your application.

Please note that once you have submitted your application, it will not be considered until you have uploaded your CV and transcripts.

Funding Notes

Level of Award: We have a number of scholarships available. The annual stipend will be approx. £15,000 and full fees will be paid for a period of between 3 to 3.5 years.

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