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The University of Manchester Featured PhD Programmes

(BBSRC DTP) Enzymes with an Expanded Amino Acid Alphabet


Department of Chemistry

About the Project

The ability to rationally design an enzyme for any desired transformation would have major impacts across the pharmaceutical and wider chemical sectors, leading to more efficient and sustainable synthetic routes to high value chemicals. The combination of computational enzyme design and directed evolution is currently the most attractive strategy to achieve this ambition. However, the limited range of functional groups presented by the genetic code (i.e. 20 amino acids) restricts the range of catalytic mechanisms which can be installed into designed active sites, thus severely limiting the repertoire of chemical transformations accessible.
Advanced protein engineering technologies available in our laboratory now allow us to install non-canonical ‘chemically inspired’ amino acids into enzyme active sites, thus greatly expanding upon the limited range of functionality accessible with Nature’s genetically encoded residues. We have recently combined this genetic code expansion technology with computational enzyme design and laboratory evolution to create the first enzyme that operates via a non-canonical organocatalytic mechanism (Nature 2019, 570, 219). In this PhD studentship, we will now expand ambitiously upon this early success, to demonstrate that the integration of non-canonical amino acids into computational design and directed evolution workflows can lead to the creation of enzymes with novel catalytic mechanisms and new activities. The design of new functional amino acids will be inspired by small molecule organocatalysts which are able to promote a plethora of valuable transformations not observed in Nature. Our approach merges the complementary disciplines of organocatalysis and biocatalysis, combining the mechanistic and functional versatility of small molecule systems with the enormous rate accelerations and reaction selectivities achievable within evolvable protein scaffolds.
This is a highly interdisciplinary project at the cutting edge of enzyme design and engineering research, and will provide the student with expertise in advanced protein engineering methods, directed evolution, organic synthesis and structural biology, skills that are highly relevant to a future career in the pharmaceutical and wider chemical industry.

https://www.greenresearchgroup.co.uk/
https://www.research.manchester.ac.uk/portal/anthony.green.html
https://www.research.manchester.ac.uk/portal/sam.hay.html

Entry Requirements:
Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.

UK applicants interested in this project should make direct contact with the Principal Supervisor to arrange to discuss the project further as soon as possible. International applicants (including EU nationals) must ensure they meet the academic eligibility criteria (including English Language) as outlined before contacting potential supervisors to express an interest in their project. Eligibility can be checked via the University Country Specific information page (https://www.manchester.ac.uk/study/international/country-specific-information/).
If your country is not listed you must contact the Doctoral Academy Admissions Team providing a detailed CV (to include academic qualifications – stating degree classification(s) and dates awarded) and relevant transcripts.

Following the review of your qualifications and with support from potential supervisor(s), you will be informed whether you can submit a formal online application.

To be considered for this project you MUST submit a formal online application form - full details on how to apply can be found on the BBSRC DTP website http://www.manchester.ac.uk/bbsrcdtpstudentships

Equality, diversity and inclusion is fundamental to the success of The University of Manchester, and is at the heart of all of our activities. The full Equality, diversity and inclusion statement can be found on the website https://www.bmh.manchester.ac.uk/study/research/apply/equality-diversity-inclusion/

Funding Notes

Funding will cover UK tuition fees/stipend only. The University of Manchester aims to support the most outstanding applicants from outside the UK. We are able to offer a limited number of bursaries that will enable full studentships to be awarded to international applicants. These full studentships will only be awarded to exceptional quality candidates, due to the competitive nature of this scheme.

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