Supramolecular capsules for biomimetic recognition and creating artificial enzymes

A Crick funded PhD position for the 2021 programme in the lab of Charlie McTernan.

Project background and description

We are a synthetic chemistry group working in supramolecular and biological chemistry, and nanotechnology. We work in the Francis Crick Institute in London, and at King's College London.

Our research looks at how we can apply Supramolecular Chemistry in Biological settings. Supramolecular Chemistry is the study of intermolecular, non-covalent interactions. These non-covalent interactions are critical to protein folding, DNA base pairing, and cellular signalling. Supramolecular Chemistry applies these same principles to create artificial systems capable of performing complex tasks. [1-3]

The McTernan Group aims to apply recent breakthroughs in artificial molecular machines and metal-organic capsules in biologically relevant settings. We work with rotaxanes, catenanes and capsules to synthesise functional architectures, creating de novo catalytic enzyme analogues, artificial cellular receptors, and generating targeted drug delivery vehicles.

Supramolecular Chemistry is often inspired by the functionality and complexity of nature. Whilst great strides have been made towards achieving artificial analogues of biological molecular machines, synthetic systems have been unable to match the specificity and directionality vital to the concerted processes of biology. This PhD project will develop new tools to bridge this gap, creating nano-scale capsules, formed from biological sequence polymers. [4, 5]

By using self-assembled architectures to develop the hitherto unexplored ability of sequence polymers to create precisely defined internal nanospaces within metal-organic capsules, we will be able to mimic the precise binding of biological systems, using vastly simplified synthetic systems. We will combine the information-density of biological systems with the well-defined cavity of metal-organic capsules, creating capsules with a ground-breaking array of functions, enabled by precise and targeted functionalisation of the capsule. We will create catalytic pockets, with cooperative catalysis between residues – that is, design de novo enzyme mimics, able to replace faulty enzymes, and generate capsules able to bind specific, biologically relevant, guests. We will append short targeting peptides to these capsules, allowing us to use them for directed cargo delivery in vivo.

Candidate background

This project would suit candidates with a background in chemistry or biochemistry, and an interest in working at the interface between disciplines.

References

1.         Erbas-Cakmak, S., Leigh, D.A., McTernan, C.T. and Nussbaumer, A.L. (2015)

            Artificial molecular machines.

            Chemical Reviews 115: 10081-10206. PubMed abstract

2.         Erbas-Cakmak, S., Fielden, S.D.P., Karaca, U., Leigh, D.A., McTernan, C.T., Tetlow, D.J. and Wilson, M.R. (2017)

            Rotary and linear molecular motors driven by pulses of a chemical fuel.

            Science 358: 340-343. PubMed abstract

3.         Fielden, S.D.P., Leigh, D.A., McTernan, C.T., Pérez-Saavedra, B. and Vitorica-Yrezabal, I.J. (2018)

            Spontaneous assembly of rotaxanes from a primary amine, crown ether and electrophile.

            Journal of the American Chemical Society 140: 6049-6052. PubMed abstract

4.         McTernan, C.T., Ronson, T.K. and Nitschke, J.R. (2019)

            Post-assembly modification of phosphine cages controls host-guest behavior.

            Journal of the American Chemical Society 141: 6837-6842. PubMed abstract

5.         McTernan, C.T., De Bo, G. and Leigh, D.A. (2020)

            A track-based molecular synthesizer that builds a single-sequence oligomer through iterative carbon-carbon bond formation.

            Chem 6: 2964-2973.