Beyond AlphaFold: Experimental and computational folding of a de novo membrane protein

University of Bristol

About the Project

It has been suggested that the advent of AlphaFold has now “solved the protein folding problem”. In fact, understanding the precise steps that a protein must take in order to adopt a specific, functional threedimensional fold remains a very active area of research. In particular, the folding behaviour of integral membrane proteins – which constitute about one-quarter of all the proteins in nature – is still quite unclear. A deeper comprehension of membrane protein folding and assembly is very important as part of our fundamental knowledge of protein science, but also for appreciating how mis-folding might occur in human disease, and how folding processes can be exploited in protein design and synthetic biology. The Curnow lab has recently developed a man-made, synthetic membrane protein that offers a new opportunity to study folding processes at the molecular level. This unique protein can be made by living bacterial cells. It is trafficked to the bacterial cell membrane where it binds tightly to the catalytic cofactor heme. This means that we now have, for the first time, a simple and extremely robust mimic of the heme-binding bioenergetic proteins that power biology via respiration and photosynthesis.

In this PhD project, the student will combine computational and laboratory methods to understand the biosynthesis of our artificial cytochrome. The laboratory work will move out of the complex cell environment and instead use well-controlled in vitro systems to manufacture the protein. This approach allows us to break down the folding and assembly process into specific, discrete steps and so to unpick exactly what is happening at each step. It will provide an unprecedented insight into the formation of the protein-heme complex, and once the methods are established we can then apply this same technique to natural proteins too. Surprisingly, despite their critical importance to cellular life, bioenergetic proteins have not previously been closely studied in this way. The other aspect of the studentship is to build a computer model of the entire folding process. Such molecular dynamics methods have not previously been possible because of the computational demands of simulating a realistic lipid membrane. However, new methodological developments and increasing computational power now put this long-held goal within reach. This project thus offers an exciting combination of theory, experiment and simulation that will be used to address one of the remaining ‘grand challenges’ in protein science.

Our aim as the SWBio DTP is to support students from a range of backgrounds and circumstances. Where needed, we will work with you to take into consideration reasonable project adaptations (for example to support caring responsibilities, disabilities, other significant personal circumstances) as well as flexible working and part-time study requests, to enable greater access to a PhD. All our supervisors support us with this aim, so please feel comfortable in discussing further with the listed PhD project supervisor to see what is feasible.

How to apply   

To apply, please read the information on the prospectus page of the programme – South West Biosciences Doctoral Training Partnership (BBSRC) Study at Bristol University of Bristol, including the Admissions Statement and the English proficiency requirements. 

Then, enter the University of Bristol application portal: Start your application Study at Bristol University of Bristol and select the programme “South West Biosciences Doctoral Training Partnership (PhD)”. You can select any of the entry points, applying to up to 3 projects, although the start date will be in September 2024. 

The application deadline is 11:59 pm on 04/12/2023. 

You can find more information at the link: How to apply – SWBiosciences Doctoral Training Partnership, selecting “University of Bristol”. 

About 

The South West Biosciences Doctoral Training Partnership (SWBio DTP) is led by the University of Bristol, together with the Universities of Bath, Cardiff and Exeter, alongside Rothamsted Research.  This partnership also includes the following associate partners; Marine Biological Association (MBA), Plymouth Marine Laboratory (PML), SETsquared Bristol, Swansea University, UCB Pharma and University of the West of England (UWE).  

These institutions represent a distinctive group of bioscience research staff and students, with established international, national and regional networks, and widely recognised research excellence. As research leaders, we have a strong track record in advancing knowledge through high-quality research and teaching, in partnership with industry and the government.  

The programme particularly aims to provide students with outstanding interdisciplinary research training within the following areas – advancing the frontiers of bioscience discovery; bioscience for sustainable agriculture and food; bioscience for an integrated understanding of health. Importantly this research training is also underpinned by transformative technologies, allowing our students to expand the boundaries of their research through innovative tools, technologies and approaches.  Our students will be exposed to the expertise of all the partners by visiting / using their facilities, taking part in joint conferences, workshops and taught modules. To further the collaboration between the partnership, cross-institutional PhD projects will be featured that build on the expertise of each partner.  

Programme Overview  

Programme – SWBiosciences Doctoral Training Partnership  

If you have any questions on the scheme, you are welcome to contact Sue Summerill (Graduate Administration Manager, Faculty of Life Sciences) with any questions –

For project-related enquiries, please contact the project supervisor. 

To help us track our recruitment effort, please indicate in your email – cover/motivation letter where (jobs-near-me.eu) you saw this job posting.