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Sequence specific asymmetric catalysis with DNA-peptide-copper hybrid catalysts

Principal Supervisor: Dr Anna Peacock - School of Chemistry

Co-supervisor: John Fossey

PhD project title: Sequence specific asymmetric catalysis with DNA-peptide-copper hybrid catalysts

University of Registration: University of Birmingham

Project outline:

This PhD project will develop novel hybrid catalysts coupling DNA, peptide chemistry and coordination chemistry, for applications in asymmetric transition-metal catalysis and sensing. This work is inspired by Nature’s catalysts, enzymes, which have been perfected by evolution to perform reactions under mild conditions and with enviable asymmetric control and selectivity. Chemical catalysts, on the other hand, offer more diversity in terms of reactivity, albeit their simpler design and smaller scaffolds, means that reaction outcomes (specifically with respect to chirality) are more difficult to control. However, a recent report by Roelfes and Feringa demonstrated that asymmetric catalysis could be induced in small molecule copper complexes on association with chiral DNA.[1] However, this was achieved by non-specific interactions and is therefore triggered in the presence of any sequence of DNA. This project instead couples aspects of these copper complexes with peptides inspired by DNA transcription factors, so as to evolve hybrids, which bind, and therefore respond catalytically, in a sequence selective fashion to DNA. Prior work in the Peacock group has shown that copper hybrid complexes with GCN4, a yeast transcription factor, can be designed which retain this crucial sequence selective DNA binding, whilst bringing the copper complex in close proximity to the DNA scaffold.[2]

This project will investigate asymmetric outcomes as a result of sequence specific DNA binding of hybrid complexes (see Figure), by exploiting protein-DNA biomolecular recognition as an activation mechanism, coupled with chemical catalysis. This project will utilise the knowledge and expertise in the Peacock group in DNA peptide scaffolds[2,3] and couple that to asymmetric catalysis knowledge in the group of Dr John Fossey,[4, 5] to develop new catalysts underpinned by DNA. As a result of sequence-specific asymmetric catalysis it will be possible to produce chiral molecules in response to a specific sequence. Modulation of chirality and product outcomes permits drug-delivery/production (asymmetric catalysis) and reported molecule production (sensing), offering a biocompatible, unique and readily translatable approach to probe and respond to specific DNA sequences.

Pic1

Figure 1 Cartoon schematic of proposed copper-GCN4 peptide hybrid capable of sequence selective asymmetric catalysis when bound to the GCN4 DNA target site.

References: 

  1. Roelfes, G.; Boersma, A. J.; Feringa, B. L. “Highly enantioselective DNA-based catalysis” Chem. Commun., 2006, 635.
  2. Oheix, E.; Peacock, A. F. A. “Metal-ion-regulated miniature DNA-binding proteins based on GCN4 and non-native regulation sites” Chem. Eur. J., 2014, 20, 2829.
  3. 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.
  4. He, F.-S.; Jin, J.-H.; Yang, Z.-T.; Yu, X.; Fossey, J. S.; Deng, W.-P. ACS Catalysis 2016, 6, 652.
  5. Brittain, W. D. G.; Buckley, B. R.; Fossey, J. S.,Chem. Commun. 2015, 51 (97), 17217-17220.

BBSRC Strategic Research Priority: Industrial Biotechnology and Bioenergy

Techniques that will be undertaken during the project:

The student will gain training and considerable experience in a range of techniques including, peptide design, synthesis and chemical functionalization, solution spectroscopic techniques (such as ultraviolet-visible, fluorescence and circular dichroism spectroscopy), gel electrophoresis, DNA chemistry, chemical synthesis and asymmetric catalysis. Interdisciplinary and transferable skills will be gained through collaboration across two laboratories and the network of collaboration across campus both supervisors have cultivated.

Contact: Dr Anna Peacock, University of Birmingham