Hydrogen-transfer reactions involving hydride, hydrogen atom or proton transfers are ubiquitous in enzyme-catalysed reactions. It is now well established that these reactions can occur via a mechanism involving some degree of quantum mechanical tunnelling (QMT), and thus are a feature of quantum biology. The QMT contribution is highly variable and is thought to correlate with kinetic isotope effects (KIEs) measured on these reactions typically with hydrogen and deuterium. An open question remains whether there has been evolutionary pressure to select for QMT during enzyme catalysis. Theoretically, it is possible to increase the rate of an enzyme-catalysed H-transfer reaction by increasing the tunnelling contribution, so this could offer a fitness advantage. However, typical strategies to increase the tunnelling contribution are also likely to increase the rate of classical (over-the-barrier) H-transfer.
In this project we aim to combine experimental studies of H-tunnelling in enzyme catalysed reactions (Hay’s expertise) with directed evolution (DE; Green’s expertise) and computational chemistry (Hay and Johannissen’s expertise). DE will be performed on enzyme(s) that utilise rate-limiting H-transfers during their catalytic mechanism. High- and medium-throughput screening methods that select for enzyme activity with both protiated and deuterated substrates will be used in order to allow parallel evolution of enzymes evolved specifically for H- and D- transfer. This will allow a new and more comprehensive approach to the exploration of the relationships between H- and D- transfer kinetics and QMT during enzyme evolution and will also establish whether selecting for improved D-transfer kinetics provides new avenues for improving enzyme performance, e.g. for improvement of industrial biocatalysts.
The project is highly interdisciplinary and the student will gain experience in directed evolution (Green), enzyme kinetics and structural biology (Green, Hay) and computational chemistry (Hay, Johannissen). The supervisors are co-localised in the Manchester Institute of Biotechnology (MIB; www.mib.ac.uk) at the University of Manchester. For further information, please contact Professor Sam Hay ([Email Address Removed]).
www.manchester.ac.uk/research/sam.hay
Eligibility
Applicants must have obtained or be about to obtain a First or Upper Second class UK honours degree, or the equivalent qualifications gained outside the UK, in an appropriate area of science, engineering or technology.
Before you Apply
Applicants must make direct contact with preferred supervisors before applying. It is your responsibility to make arrangements to meet with potential supervisors, prior to submitting a formal online application.
How To Apply
To be considered for this project you MUST submit a formal online application form - full details on eligibility how to apply can be found on the BBSRC DTP website https://www.bmh.manchester.ac.uk/study/research/bbsrc-dtp/
Your application form must be accompanied by a number of supporting documents by the advertised deadlines. Without all the required documents submitted at the time of application, your application will not be processed and we cannot accept responsibility for late or missed deadlines. Incomplete applications will not be considered. If you have any queries regarding making an application please contact our admissions team [Email Address Removed]
Equality, Diversity and Inclusion
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/
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