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Assembly & Dynamics of Bacterial Membrane Protein Structures

Primary Supervisor: Dr Phillip Stansfeld, School of Life Sciences

Secondary supervisor(s): Depending on the project there are a number of colleagues who would be most appropriate for co-supervision, including David Roper, Allister Crow, Liz Fullam, Chris Dowson, Andrew Lovering, Tim Knowles and others

PhD project title: Developing a dynamic molecular description of the Bacterial Cell Envelope

University of Registration: University of Warwick

Project outline:

The development of the Artificial Intelligence protein-folding software, AlphaFold2, has enabled the accurate computational determination of over 360,000 monomeric protein structures; with this expected to rise to over 130,000,000 in the next year. An secondary benefit of this methodology is the ability to also model both homo- and heteromeric complexes. This is especially true for bacterial proteins, where operon-based information may be used to combine sequences of individual proteins, based on the proximity of the genes within the chromosome. This enables co-evolutionary data to be acquired, where amino acid residue positions that vary in tandem may be inferred as potential contact points within the folded protein structure. In short, this provides a blueprint for how AlphaFold may assemble the protein structure and/or complex.

~25% of these folded protein structures (~65,000) are comprised of proteins that are integral to lipid membranes. In bacteria, these proteins fullfill key tasks of, e.g., selective uptake of nutrients, processing of secreted proteins or expulsion of toxic compounds, such as antibiotics; and therefore form current and future targets for novel antimicrobials through inhibition of these processes.

The overall aim of this proposal is to provide a structural description of bacterial complexes that form within the cell envelope; the front-line to a bacterium’s defence. By understanding the three-dimensional details of how these complexes form, we have a better grasp of the fundamental processes performed by these proteins, and therefore have an improved understanding of how one can develop novel antimicrobial inhibitors.

BBSRC Strategic Research Priority: Understanding the Rules of Life: Microbiology & Structural Biology. Integrated Understanding of Health: Pharmaceuticals

Techniques that will be undertaken during the project:

  • AlphaFold2-based protein folding.
  • Molecular Dynamics (MD) simulations.
  • Structural Bioinformatics.
  • Python-based programming.

Contact: Dr Phill Stansfeld, University of Warwick