Hybrid Mass Spectrometry Methods to Determine Structure Activity Relationships for Photocatalytic Enzymes


   Department of Chemistry

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  Prof P Barran, Prof N Scrutton, Dr Derren Heyes  No more applications being accepted  Funded PhD Project (UK Students Only)

About the Project

This project will use ion mobility mass spectrometry, photoactivation, soft landing and single molecule imaging to understand enzyme structure function relationships. You will also use HTS MS methods to determine the catalytic activity of these enzymes by directly monitoring substrate conversion. By combing the outputs from structural mass spectrometry and soft-landing imaging with the activity of the enzymes in question this project will help to define ‘minimal photocatalytic units’. This project will assist the rule-based design of photo-biocatalysts to open up new and high-energy catalytic reaction pathways. In the project you will explore a range of designed flavin dependent photocatalysts to obtain mechanistic and structural information from advanced mass spectrometry methods.

You will learn how to use mass spectrometry to measure the mass and the conformation of proteins. Using photoactivation coupled to ion mobility mass spectrometry you will be able to determine conformational changes that occur due to light activation. In this project you will combine this with a novel soft-landing stage, which will allow the proteins to be subsequently visualised with electron microscopy. Using desorption electrospray ionisation coupled to mass spectrometry you will develop methods to monitor reaction rates. You will become an expert in structural mass spectrometry as applied to biological systems.

Background

We are taking a unique interdisciplinary approach to decipher mechanistic rules that will enable us to repurpose any flavin-containing enzyme as a photo-biocatalyst through ‘top-down’ engineering of natural enzymes and ‘bottom up’ de novo design of robust photobiocatalytic frameworks. In doing so, we will maintain and expand the beneficial, highly selective, natural and engineered specificities of thermally activated enzymes, which provides major advantages over the limited photocatalytic transformations that can be achieved with small molecule photocatalysts. Fundamental mechanistic understanding of flavin-containing photo-biocatalysts will emerge, coupled with data-driven inferences derived from the sequences, structures and functional properties of natural and engineered proteins.

The studentship is part of a larger BBSRC funded programme grant on photoactivated biocatalysis led by the Scrutton group and involving collaborators at the University of Manchester, Bristol and Edinburgh. We are looking for motivated students with interests in studying for a PhD in photobiocatalysis, with interests in protein structure and function, analytical science, method development, biophysics and biocatalysis. It builds on a body of work that includes the development of the lightfootprinting technique where ions are excited during the electrospray process and the conformational and/or stoichiometric changes that occur are monitored with ion mobility mass spectrometry (13) as well as HTS MS methods. (4)

In addition to the direct experimental skills you obtain from this project, you will develop skills in project and organisational management, data presentation and experimental design.

The research collaboration: The Barran labs are based in the Manchester Institute of Biotechnology (http://www.mib.ac.uk), an excellent academic environment for research in biocatalysts  and mass spectrometry development with unique facilities and multidisciplinary research programmes.

The Research Environment The University of Manchester has long pioneered the use and development of mass spectrometry, The Department of Chemistry is ranked in the top five for research in the UK and the MIB is at the forefront of translating basic chemical biology and biotechnology. Analytical technologies are relied on by researchers throughout physical sciences and at Manchester are also at the forefront of research, as exemplified by the Michael Barber Centre for Collaborative Mass Spectrometry MBCCMS which is world renowned for the use and development of mass spectrometry and in particular ion mobility mass spectrometry. This forms a research flagship within the Mass Spectrometry and Separations Science Facility of the Faculty of Science and Engineering and is located in the Manchester Institute of Biotechnology.

The MBCCMS is homed in modern state-of-the-art laboratories, with a critical mass of expert support staff to run and maintain the equipment as well as to fully explore the new capabilities, to train new users and to manage the access and cost recovery models. Approximately 40 research groups at the UoM make use of the facilities of the MBCCMS, and there are a similar number of external users from both academia and Industry. Researchers in the MCCMS have access to 28 mass spectrometers and you will be able to make full use of them too!

Entry Requirement

Applicants should have or expect to achieve at least a 2.1 honours degree (or equivalent) in chemistry, biophysics, chemical engineering or biochemistry or a closely related subject. Applications from individuals with direct industrial experience will be especially welcomed. You would be expected to have laboratory experience of method development and expertise in sample handling and analytical procedures.

How to apply:

You will need to submit an online application through our website here: https://uom.link/pgr-apply

When you apply, you will be asked to upload the following supporting documents: 

• Final Transcript and certificates of all awarded university level qualifications

• Interim Transcript of any university level qualifications in progress

• CV

• You will be asked to supply contact details for two referees on the application form (please make sure that the contact email you provide is an official university/ work email address as we may need to verify the reference)

• English Language certificate (if applicable)

If you have any queries regarding making an application please contact our admissions team [Email Address Removed]

Before you apply

We strongly recommend that you contact the supervisor to discuss the application before you apply. 

Equality, diversity and inclusion is fundamental to the success of The University of Manchester, and is at the heart of all of our activities. We know that diversity strengthens our research community, leading to enhanced research creativity, productivity and quality, and societal and economic impact. We actively encourage applicants from diverse career paths and backgrounds and from all sections of the community, regardless of age, disability, ethnicity, gender, gender expression, sexual orientation and transgender status.

We also support applications from those returning from a career break or other roles. We consider offering flexible study arrangements (including part-time: 50%, 60% or 80%, depending on the project/funder). 

Agriculture (1) Biological Sciences (4) Chemistry (6) Medicine (26) Physics (29)

Funding Notes

This 3.5 year PhD project is fully funded by The Department of Chemistry and is available to home students. The funding covers tuition fees and a tax free stipend set at the UKRI rate (£18,622 for 2023/24). The successful applicant will work at Waters in Wilmslow. The start date will be no later than October 1st 2024.

References

1. R. J. Kutta et al., Nature Communications. 6, 7907 (2015).
2. I. S. Camacho et al., Proceedings of the National Academy of Sciences of the United States of America. 116 (2019), doi:10.1073/pnas.1813254116.
3. I. S. Camacho et al., CHEMICAL SCIE

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