Current computational design, aimed at improving the activity of a catalytic mechanism, focuses on identifying its transition states using quantum mechanics. These calculations only provide the total system’s energy rather than that of atoms/fragments. Properly defined fragment energies open the exciting prospect of enhancing and guiding experimental enzymatic design a priori (rather than as an afterthought). The PI’s has developed such a fragment method: REG-IQA (Relative Energy Gradient1 - Interacting Quantum Atoms2). REG-IQA rigorously identifies which enzymatic fragment is most responsible for the total enzyme’s action. This enables REG-IQA to interpret the value of a single interaction. This application of REG-IQA is in sharp contrast to traditional energy decomposition methods acting ad hoc offering understanding after significant experimental study (directed evolution, screening, etc.) or by relying on multiple reactions involving a range of substrates or residues in order to establish trends.

REG-IQA has been used to rationalise experimental observations of various enzymes, including GTPases, HIV-1 proteases, and prFMN-dependent decarboxylases. This demonstrates the ability of REG-IQA to determine key interactions that drive enzyme activity, while being consistent with experiment. For example, when applied to the formation of an adduct intermediate in the catalytic cycle of the prFMN-dependent decarboxylase AnFdc1, steric hindrance of residues above the intermediate was implicated in increasing the turnover of adduct formation and cleavage. This explanation reaffirmed earlier studies4,3 showing AnFdc1’s preference for bulkier substrates, while mutations introduced through directed evolution resulted in increased steric hindrance in the active site.

We will apply REG-IQA to elucidate the catalytic mechanisms of a new family of SNAr enzymes recently developed within the Green lab (CoI). SNAr reactions are amongst the most widely used processes in the pharmaceutical and agrochemical industries5 but are not commonly found in natural biosynthesis. Work within the Green lab has recently developed a biocatalytic solution to these reactions (paper accepted), by engineering designer enzymes capable of catalysing a C-C and C-O bond forming SNAr transformations with excellent rate enhancements and stereocontrol (Fig. 1b). Structural and biochemical analysis provided insights into the substrate binding modes and key active site residues leading to efficient catalysis. As these transformations are likely to proceed via a single transition state, these SNAr enzymes are excellent candidates for REG-IQA. Gaining further mechanistic insights with deeper analysis of beneficial enzymatic interactions with given SNAr transition states will greatly facilitate future library design efforts, expediting the generation of new SNAr biocatalysts with enhanced properties.

Eligibility

Applicants must have obtained or be about to obtain a minimum Upper Second class UK honours degree, or the equivalent qualifications gained outside the UK, in an appropriate area of science, engineering or technology.

International applicants

We are only able to offer a limited number of full studentships to applicants outside the UK. Therefore, full studentships will only be awarded to exceptional quality international candidates due to the competitive nature of this scheme.

International applicants must ensure they meet the academic eligibility criteria (including English language) before applying. Visit our ‘Eligibility and entry requirements’ page to find out more about our English language requirements.

Before you Apply

Browse our BBSRC NWD in Bioscience projects and discover one you're passionate about that matches your interests, ambitions and goals.

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

All applications should be made via our specific BBSRC NWDP in Bioscience online application form. This is a separate application process specifically for all candidates for this scheme. Applications should not be made through either university’s usual online application system.

You must submit your application form along with the required supporting documents by the deadline date. You can select up to two projects on one single application, noting the title of each project from the advert and the supervisor name. This can include two projects from one institution or a project from each institution.

Before you complete your application you should prepare the following supporting documents:

·            CV

·            Personal statement

·            Degree certificates and transcripts (if your qualification is still pending, please ensure this is clear on your application form and you can send this to us at a later date)

·            Two references

·            Evidence of English language qualifications (if completed)

Complete the application form: https://forms.office.com/e/HVXALrVa0P

Once you have completed your application, you'll receive a confirmation email and             you should reply to this email with all of your supporting documentation as soon as possible to: [email protected]

Deadline: Friday, 31 January 2025, 5pm

Late or incomplete applications will not be considered.

If you need help with this stage of the process, or have any queries regarding your eligibility (such as if you achieved unexpectedly low degree results due to extenuating circumstances), please contact the Doctoral Admissions team for advice at [email protected] .

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.