Direct observation of the structure and function of cooperatively assembled membrane spanning pores formed by antimicrobial peptides.

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Project Description:The challenge of antimicrobial resistance has ignited interest in understanding the mechanisms of antimicrobial peptides (AMPs) of the innate immune system. AMPs generally form membrane-spanning pores as part of their bactericidal activity, however, the precise mechanisms of assembly and function remain poorly understood. This is in part due to the challenges of interfacing functional model membrane systems with techniques for their interrogation.This project will combine multiple single molecule imaging techniques applied to model membranes [1] to study the mechanisms of peptide interaction of established and novel AMPs. By studying at the single molecule level we can gain otherwise inaccessible insight into the mechanisms of assembly of membrane spanning pores.With this approach you will study the synergistic activity of Magainin-II/PGLa by quantitative three-colour single-molecule imaging to understand the nature of peptide-peptide interactions [2] in pore formation, and quantify the activity dynamics of assembled pores [3]. You will also extend these techniques to novel AMPs developed by the team [4]. Understanding the mechanism of action of such pores will provide fundamental understanding into molecular self-assembly, alongside determining structure-function relationships of the pore itself, fundamental to design novel AMPs. The tested peptides possess cytotoxic activity against cancer cells, so this research may create opportunities for next generation therapeutics and drug delivery systems. Once peptide characterisation is achieved in model membranes you will have the opportunity to study their effect in 2-and-3D cell models.Research Environment: You will work within a multidisciplinary team at the physical-life science interface, gaining experience across disciplines from biochemistry, single molecule techniques, membrane synthetic biology and cell biology. You will initiate the research with rotational projects of peptide and protein synthesis (Jin), and single molecule membrane imaging (Castell), providing a foundation for the research project. The supervisory team have an excellent track record in supervision and publication, alongside a unique combination of expertise from which you and the project will benefit, - e.g. artificial membranes and single molecule methods (Castell), protein/peptide biochemistry (Jin), AMPs and cell biology (Jones) and tissue model and biological imaging (Watson). We applications from enthusiastic scientists with appropriate knowledge/experience/ideas in some of the areas outlined (biochemistry|protein/peptide handling|biological physics|physical chemistry|fluorescence) with an eagerness to learn across disciplines and develop in areas new to the candidate. We do not expect prior experience in all areas. Talented and enthusiastic candidates from all backgrounds are encouraged to apply. We recognise that diversity within a team provides a greater range of experience, perspectives and ideas to draw upon when tackling problems and informing decisions.