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Understanding the Maturation and Localisation Pathways within the Bacterial Cell Envelope

Primary Supervisor: Dr Phillip Stansfeld, School of Life Sciences

Secondary supervisor: Professor David Roper

PhD project title: Understanding the Maturation and Localisation Pathways within the Bacterial Cell Envelope

University of Registration: University of Warwick

Project outline:

One of the fundamental challenges in biological sciences is to visualise the dynamics of biomolecular machines in high-resolution detail. With the increasing threat of anti-microbial resistance, we are especially interested in bacterial membrane proteins. Knowledge of the three-dimensional structures and dynamics of proteins involved in essential processes provides the physical details of potentially viable targets for killing drug-resistant, pathogenic bacteria.

The main focus of this project is to characterise the key membrane protein components of critical bacterial maturation and localisation pathways, with the future ambition of developing novel bactericidal or bacteriostatic therapeutics.

The project will involve the study of the enzymes and transporters involved in protein, peptidoglycan, lipid and/or lipopolysaccharide biosynthesis. These studies will allow you to acquire skills in structural bioinformatics, multiscale molecular simulations and computational chemistry to elucidate the dynamic interplay between the membrane proteins and their substrates, products and known inhibitors.

The results will establish in full molecular detail how these crucial molecular units are processed and transported by the intramembrane proteins of the pathway. The data will ascertain the optimal means to enable the development of novel antibiotics through inhibition of these molecular processing systems.

The focus of the project will be on one of the systems listed below, with the potential to study more than one system for the full studentship:

  1. Transport of lipopolysaccharide and lipids to and from the bacterial outer membrane.
  2. Maturation and localization of lipoproteins involved in development and pathogenicity.
  3. Processes of protein secretion through Sec or Tat and maturation by signal peptidases.
  4. Production and transport of the peptidoglycan components of the bacterial cell wall.

References:

  1. Corey RA, Vickery ON, Sansom MSP,Stansfeld PJ. Insights into Membrane Protein-Lipid Interactions from Free Energy Calculations. Chem. Theory Comput. 2019
  2. Caffalette CA, Corey RA, Sansom MSP, Stansfeld PJ, Zimmer J. A lipid gating mechanism for the channel-forming O antigen ABC transporter. Nat Commun. 10(1):824
  3. Newport TD, Sansom MSP, Stansfeld PJ. MemProtMD: A Resource for Membrane Protein Structures and their Lipid Interactions. Nucleic Acids Research.
  4. Stansfeld PJ. Computational studies of membrane proteins: from sequence to structure to simulation. Current Opinion in Structural Biology. 2017; 45: 133-141.
  5. Gu Y, Li H, Dong H, Zeng Y, Zhang Z, Paterson NG, Stansfeld PJ, Wang Z, Zhang Y, Wang W, Dong C. Structural basis of outer membrane protein insertion by the BAM complex. Nature2016; 531:64-9.
  6. Vogeley, L, El Arnaout, T, Bailey, J,Stansfeld PJ, Boland, C, Caffrey, M. Structural basis of lipoprotein signal peptidase II action and inhibition by the antibiotic globomycin. Science2016; 351:876-80.

BBSRC Strategic Research Priority: Understanding the Rules of Life: Structural Biology

Techniques that will be undertaken during the project:

  • Computational Biochemistry
  • Molecular Modelling
  • Molecular Simulations
  • Bioinformatics
  • Protein-Folding
  • in silico Binding-Energy Calculations
  • Programming skills

Contact: Dr Phillip Stansfeld, University of Warwick