Project Outline

The development of the protein-folding software, AlphaFold2, has enabled the computational determination of over 130 million monomeric protein structures. One can also use this method to model both homo- and heteromeric complexes. This is especially true for bacterial proteins, where organism and operon-based information may be used to provide a blueprint for how AlphaFold may assemble the protein structure and/or complex. An example of one of our computer-modelled complexes is shown below. This is the target for beta-lactam inhibitors, e.g. penicillin.

One quarter of the 130 million folded protein structures are expressed within 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 and dynamic description of bacterial complexes that form within the cell envelope, embedded within lipid membranes; the front-line to a bacterium’s defence.

By understanding the three-dimensional details of how these complexes form and move, we have a better grasp of the fundamental processes performed by these proteins. This therefore provides an improved understanding of how one can develop novel antimicrobial inhibitors.

References

Techniques

• AlphaFold2-based protein folding
• Molecular Dynamics (MD) simulations
• Structural Bioinformatics
• Python-based programming
• Ligand Docking
• Structure-based Drug Design