Principal Supervisor: Dr Paul DaviesLink opens in a new window

Co-supervisor: Dr Anna Peacock

PhD project title: Artificial metalloenzyme design with late transition metal active sites

University of Registration: University of Birmingham

Project outline:

This PhD project involves the rational design, preparation and assessment of artificial metalloenzymes. Nature’s catalysts, enzymes, have been perfected by evolution to perform reactions under mild conditions and with enviable asymmetric control and selectivity. However, the active sites of metalloenzymes are primarily restricted to first row transition metals, despite catalysis with heavier transition metals offering more diversity in terms of reactivity. This is primarily due to these heavier metals not being “biologically available”. This PhD project will combine the advantages afforded by both the xenobiotic and the enzymatic catalytic worlds, so as to create new biotechnology for the efficient and catalytic synthesis of complex molecules.

Xenobiotic catalytic sites will be engineered into increasingly complex and structured peptide and protein assemblies. This includes, but is not limited to de novo designed miniature artificial protein scaffolds, specifically coiled coils (see Figure). The resulting artificial metalloenzymes with xenobiotic active sites will be screened for asymmetric catalysis, and used to establish key structure-function relationships. This is a multidisciplinary project incorporating elements of asymmetric chemical catalysis and synthetic biology.

Figure 1 An example of a proposed artificial metalloenzyme with a xenobiotic gold active site.

References:

[1] Peacock, A. F. A.; Bullen, G. A.; Gethings, L.; Williams, J. P.; Kriel, F. H.; Coates, J. “Gold-Phosphine Binding to De Novo Designed Coiled Coil Peptides”, J. Inorg. Biochem., 2012, 117, 298.

[2] Simm, P. E, Sekar, P, Richardson, J, Davies, P. W. “Gold(I)-Catalyzed Synthesis of 3-Sulfenyl Pyrroles and Indoles by a Regioselective Annulation of Alkynyl Thioethers” ACS Catal. 2021, 6357.

[3] Berwick, M. R.; Lewis, D. J.; Pikramenou, Z.; Jones, A. W.; Cooper, H. J.; Wilkie, J.; Britton, M. M.; Peacock, A. F. A. “De Novo Design of Ln(III) Coiled Coils for Imaging Applications” J. Am. Chem. Soc., 2014, 136, 1166.

[4] Zastrow, M.; Peacock, A. F. A.; Stuckey, J.; Pecoraro, V. L. “Hydrolytic Catalysis and Structural Stabilization in a Designed Metalloprotein” Nature Chem., 2012, 4, 118.

[5] Ball, Z. T., “Designing Enzyme-like Catalysts: A Rhodium(II) Metallopeptide Case Study” Acc. Chem. Res., 2013, 46, 560.

BBSRC Strategic Research Priority: Renewable Resources and Clean Growth – Industrial Biotechnology, and Integrated Understanding of Health - Pharmaceuticals

Techniques that will be undertaken during the project:

The student will gain training and considerable experience in a range of techniques including, peptide design, transition metal catalysis, organic synthesis and chemical functionalization, solution spectroscopic techniques (such as ultraviolet-visible, fluorescence and circular dichroism spectroscopy), asymmetric catalysis, establishing structure-reactivity and structure-activity relationships, and structural chemical characterisation.

Contact: Dr Paul DaviesLink opens in a new window