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Identifying druggable binding sites in computationally-determined models of bacterial membrane proteins


Supervisors: Phill Stansfeld, Livia Bartok-Partay and Scott Midgley (Cresset)


The bacterial cell envelope is the front-line to killing drug-resistant, pathogenic bacteria. The development of AlphaFold2 and ESMFold have enabled the accurate computational determination of over 600 million protein structures. This dataset enables the study of entire bacterial membrane proteomes from the perspective of structure-based drug discovery. As part of this proposal, we aim to develop and apply methods to identify and characterize binding pockets, dock candidate small molecules and perform free energy calculations to investigate small molecule binding to folded protein structures. Our overall aim is to develop blueprints for new medicines to treat drug-resistant bacterial infections.

Links to HetSys Training:

This PhD proposal will ideally suit a student who is interested in developing novel tools and software from the perspective of studying a key biomedical problem. The student will benefit from the biochemical and simulation knowledge within the group and be able to bring to the project the skills acquired during their HetSys training, which will be crucial for the development of the robust software code and methodologies.

This project will be a collaboration across disciplinary boundaries, combining the physical sciences in Chemistry with the biological sciences of the School of Life Sciences.

At present it is uncertain how many potential binding sites exist within the structures that have been predicted by AI-based protein structure modelling software AlphaFold22. It is also not certain how many of the proteins have the potential to be drugged. Therefore, a key component of this proposal is to be able to rank and/or assess the likelihood that the identified site is both (A) suitable for binding an inhibitor and (B) critical to a biological pathway, e.g. cell wall biogenesis.

One of the ultimate ambitions is that all methodologies that are devised by this PhD proposal are suitably robust to have the potential to be incorporated into project partner Cresset's suite of tools for drug discovery. We have previously developed tools, incl. MemProtMD, CG2AT and PyLipID.


Are you interested in applying for this project? Head over to our Study with Us page for information on the application process, and the HetSys training programme.

For the 2023/24 academic year, UK Research and Innovation (UKRI) funding is open to both UK and International research students. Awards pay a stipend to cover maintenance as well as paying the university fees and providing a research training support grant. For further details, please visit the HetSys Funding Page

At the University of Warwick, we strongly value equity, diversity and inclusion, and HetSys will provide a healthy working environment dedicated to outstanding scientific guidance, mentorship and personal development. Read more about life in the HetSys CDT here.

HetSys is proud to be a part of the Physics Department which holds an Athena SWAN Silver award, a national initiative to promote gender equality for all staff and students. The Physics Department is also a Juno Champion, which is an award from the Institute of Physics to recognise our efforts to address the under-representation of women in university physics and to encourage better practice for both women and men.