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Minimal Peptide Scaffolds for Modelling and Catalysis


Project Description

Iron-sulfur clusters are ubiquitous cofactors in nature; present in a variety of metalloproteins, these clusters mediate a broad variety of essential biological processes, including electron transfer, reaction catalysis (hydrogenase, nitrogenase, etc.), oxygen-sensing and the regulation of gene expression. Radical-SAM enzymes are a superfamily of iron-sulfur metalloproteins that use a Fe4S4 cluster to reductively cleave S-adenosyl-L-methionine (SAM) to generate a radical intermediate. These enzymes employ this intermediate to perform an array of interesting chemical transformations.

This PhD project aims to develop artificial peptide metalloenzymes for the modelling of radical-SAM enzymes and to develop novel catalysts for synthesis. The candidate will explore a minimal peptide scaffold for the coordination of iron-sulfur clusters inspired by the radical-SAM family of proteins. This initial scaffold will be modified to investigate alternative electrostatic environments and probe the reactivity of the iron-sulfur unit using NMR. Extensive computational modelling will reinforce our experimental data. In parallel to these studies, our artificial metalloenzymes will be investigated as novel iron-based radical initiators for ATRP (atom-transfer radical polymerisation) and as catalysts for synthetic chemistry.

Based in the School of Chemistry, University of Nottingham, this project will provide extensive training in solid-phase peptide synthesis (SPPS), coordination chemistry (bioinorganic chemistry), analytical techniques (NMR, CD, HPLC MS) and (if requested) computational modelling.

The candidate will have a degree that qualifies them for PhD study with substantial experience in organic/biological chemistry. The studentship will be filled as soon as a suitable candidate has been found, candidates are therefore encouraged to apply as soon as possible. Prospective applicants are encouraged to contact Dr Mitchell for more details about the project.

Funding Notes

Fully funded studentship to commence before October 2020 (preferred start date 01/10/19). UK/EU students - tuition fees paid, and full stipend at the RCUK rate (£14,600 per annum for 2017/18).

Applicants should have, or expect to achieve, at least a 2:1 Honours degree (or equivalent) in Chemistry or a related subject.

A relevant Master's degree and/or experience in one or more of the following will be an advantage: organic chemistry, biological chemistry, bioinorganic chemistry, peptide chemistry, catalysis.

References

1. Sayers, J., Karpati, P. M. T., Mitchell, N. J., Goldys, A. M., Kwong, S. M., Firth, N., Chan, B. and Payne, R. J., Construction of Challenging Proline-Proline Junctions via Diselenide-Selenoester Ligation Chemistry, J. Am. Chem. Soc. 2018, 140, 13327-13334

2. Mitchell, N. J., Sayers, J., Clayton, D., Kulkarni, S. S., Goldys, A. M., Ripoll-Rozada, J., Pereira, P. J. B., Chan, B., Radom, L. and Payne, R. J., Accelerated Protein Synthesis via One-Pot Ligation- Deselenization Chemistry, Chem 2017, 2:703-71514

3. Mitchell, N. J., Malins, L. R., Liu, X., Thompson, R. E., Chan, B., Radom, L. and Payne, R. J., Rapid Additive-Free Selenocystine−Selenoester Peptide Ligation, J. Am. Chem. Soc. 2015, 137, 14011- 14014

4. Jäger, C. M. and Croft, A. K., Anaerobic Radical Enzymes for Biotechnology, Chem. BioEng. Reviews, 2018, 5(3), 143-162

5. Jäger, C. M. and Croft, A. K., Radical Reaction Control in the AdoMet Radical Enzyme CDG Synthase (QueE): Consolidate, Destabilize, Accelerate, Chemistry - A European Journal 2017, 23(4), 953-962

6. Dowling, D. P., Vey, J. L., Croft, A. K. and Drennan, C. L., Structural diversity in the AdoMet radical enzyme superfamily, Biochimica Et Biophysica Acta-Proteins and Proteomics 2012, 1824(11), 1178-1195

How good is research at University of Nottingham in Chemistry?

FTE Category A staff submitted: 42.00

Research output data provided by the Research Excellence Framework (REF)

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