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Identification, screening and scale up of enzymes in the Biocatalyst Discovery Metagenomics platform


Project Description

Background – Enzyme engineering strategies, supported by computational and molecular modelling to maximise speed and efficiency, has been shown to be a powerful tool for (semi-) rational design of enzymes.1,2 We will evaluate protein mobility/dynamics, docking/binding of substrates and calculation of free energy barriers for catalysis. These computational outcomes will guide the design of experimental directed evolution and rational/semi-rational programmes.
The target molecules in the centre will require rapid discovery and optimisation of new biocatalysts with appropriate chemo, regio- and stereo-specificities. Cross cutting technology platforms for biocatalyst discovery and optimisation (rapid biocatalyst engineering/screening) are therefore central to the overall objectives of the centre. This will be achieved using metagenomics and computational platforms to underpin Biocatalyst Discovery and Biocatalyst Design.

Aims – to design and develop a suite of computational modelling tools to maximise the speed of delivery of biocatalyst development across the centre.

Year 1 – Using the Prozomix UK metagenomics data to identify and build libraries of enzymes used across the partnership. Construction of enzyme dendrograms to capture existing state of the art across all enzyme platforms.
Year 2 – Working alongside the other researchers within the centre you will work to model the existing biocatalysts (acylases, aldolases, carboxylic acid reductases, epoxide hydrolases, reductive aminases) to design and inform the directed evolution programmes across the centre.
Year 3 – Based on initial data and benchmarking from Year 2, generate and screen large libraries of biocatalysts and their variants.
Year 4 – Iterative development of in silico design tools for implementation across the directed evolution programme within the centre.

We welcome applications from graduates with a good UK honours undergraduate degree (1st class or a high 2i), or a first degree with an additional masters degree or international equivalent, in chemistry, biochemistry, biology or another aligned science subject. Applicants should be looking for a challenging, interdisciplinary research training environment.

All applicants should send their CV and covering letter to Dr Ian Rowles (CBNM Project Manager) Applications will be reviewed as they are received until a candidate is selected; therefore candidates are encouraged to apply early.

Funding Notes

This is a 4 year studentship jointly funded by the EPSRC, AstraZenca and the University of Manchester, covering all fees and stipend (£14.777 in September 2018). Open to UK/EU applicants only.

The start date for this PhD prgramme will be September 2019.

References

1. S. Osuna et al., Acc. Chem. Res., 2015, 48, 1080.
2. A. Romero-Rivera et al., Chem Commun., 2017, 53, 284.

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