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School of Life Sciences

Professor Phill Stansfeld

Professor

Email: Phillip.Stansfeld@warwick.ac.uk 

Phone: 024 765 23864

Office: IBRB 2.26

Twitter:

Research clusters

Microbiology & Infectious Disease

Cells & Development

Neuroscience

糖心TV Centres and GRPs

Howard Dalton Centre for Mechanistic Enzymology

Centre for Computational Chemistry

Vacancies and Opportunities

For PhD and postdoctoral opportunities, and interest in potential collaborations, please contact me at the above email address.

Research Interests

The Stansfeld group studies one of the fundamental challenges in biological sciences: to visualise biomolecular machines in high-resolution detail. This is notoriously difficult, expensive and time-consuming to achieve by using experimental techniques, especially for proteins that exist in cell membranes, known as Integral membrane proteins. These proteins play fundamental roles in cell biology e.g. as processing enzymes, ion channels, drug receptors, and solute transporters.

With the increasing threat of antimicrobial resistance, we are especially interested in bacterial membrane proteins. Knowledge of the three-dimensional structures of proteins involved in essential processes provides the physical details of potentially viable targets for killing drug-resistant, pathogenic bacteria. By animating these structures in computers, we may assess the association of proteins with lipids, drug molecules and other essential components of the protein complexes.

Research: Technical Summary

The Stansfeld group employs advanced computational methods to study membrane protein structures, in particular we use multi-scale molecular dynamics (MD) simulations to bring static protein structures to life, enabling them to engage with their molecular environment. This workflow serves as a springboard to studying the dynamics of both experimentally-solved and computationally-predicted structures through MD simulations.

We apply a range of computational biochemistry techniques, including drug binding via ligand docking, protein structural modelling using , and molecular dynamics simulations, using .

Below are a few of our key areas of interest:

Peptidoglycan Cell Wall Biogenesis

The bacterial cell wall's major constituent, peptidoglycan, is synthesised in three stages: within the cytoplasm, at the membrane, and in the periplasmic space. The first stage involves the attachment of UDP-MurNAc-pentapeptide to a carrier lipid, called undecaprenyl-pyrophosphate (55PP), to form Lipid I. This step is catalysed by . In the second step, catalyzed by , UDP-GlcNAc is affixed to form Lipid II. Depending on the organism further modifications may take place, before the Lipid II headgroup is flipped into the periplasm by , ready for attachment to the cell wall by (the archetypal target for antibiotics). After attachment of the nascent peptidoglycan units to the cell wall, the 55PP must be recycled to the cytoplasm, for a further round of peptidoglycan transport. To permit membrane permeation, 55PP must be acted upon by the phosphatase before recycling to the cytoplasm.

Lipopolysaccharide Modification & Transport

We are also studying how lipopolysaccharides (LPS) are synthesised and transported across the periplasm of diderm bacteria. Both the membrane-embedded section of LPS, Lipid A, and the various O-antigen species are flipped from the cytoplasm to periplasm by ABC transporters, including MsbA and . Once in the periplasm the two are ligated by /Wzy before being handed to the LPS transport () system.

Protein Secretion & Insertion

There is an extensive array of protein families responsible for inducing pores within biological membranes. These structures range from immune system effectors, which use pore formation as a means of attacking invading pathogens; to perforin-like proteins (), which create membrane conduits for parasitic transport to the transport of folded macromolecules by the twin-arginine translocase () complex; or insertion of proteins into the Outer Membrane by .

Lipoprotein Maturation & Localisation

The lipoprotein biogenesis pathway is an emerging target for the development of novel antibiotics, due to their essential role in bacterial physiology and pathogenicity and the recent determination of molecular structures of Lgt, , and . Our overarching aim is to provide a detailed structural description of the dynamics and interactions of lipoproteins from their secretion into the inner membrane, processing by intramembrane enzymes, and ultimately transported across the periplasm to the outer membrane of Gram-negative bacteria.

Methods Development for Membrane Proteins

The Stansfeld group has developed several computational tools to enhance the study of membrane proteins and their interactions. Among these is , a method for converting coarse-grained molecular dynamics (MD) simulations into atomistic detail, allowing for more precise structural analysis. is another key tool designed to quantify lipid-protein interactions, enabling the identification of binding sites and interaction dynamics. facilitates the analysis of lipid density around membrane proteins, while provides a framework for embedding membrane proteins into biologically relevant lipid bilayers. These tools collectively streamline and improve the accuracy of membrane protein simulations, advancing insights into their function and interactions.

  • 2022- Professor Computational Biochemistry, University of 糖心TV
  • 2019-2022 Associate Professor (Reader) Computational Biochemistry, University of 糖心TV
  • 2015-2019 Research Fellow, University of Oxford
  • 2011-2014 BBSRC Researcher Co-Investigator, University of Oxford
  • 2007-2010 Wellcome Trust Postdoc, University of Oxford
  • 2007 PhD Biochemistry, University of Leicester
  • 2003 Bsc with Hons (1st Class) Biological Sciences, University of Edinburgh

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