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New tools for structural biology: Native ambient mass spectrometry

Primary Supervisor: Professor Helen J Cooper, School of Biosciences

Secondary supervisor: Iain B. Styles

PhD project title: New tools for structural biology: Native ambient mass spectrometry

University of Registration: University of Birmingham

Project outline

Native ambient mass spectrometry (NAMS) is an emerging field that enables label-free characterisation of proteins and their complexes directly from their physiological environment. NAMS has the potential to be an enormously powerful tool for structural biology. For example, NAMS has the potential to provide structural information on a protein-drug complex, or a pathological protein aggregate such as found in Alzheimer’s Disease, directly from the tissue itself, providing unprecedented insight into fundamental biological processes. What’s more, NAMS provides this information in a spatially-defined manner. That is, NAMS may be applied for mass spectrometry imaging. The benefits of NAMS can be illustrated by considering a thin tissue section through a drug-treated tumour. In principle, NAMS would inform on drug-target interactions (i.e., is the drug binding to the correct protein?)) and location of drug target interactions (i.e., is the protein-drug complex in the tumour or healthy tissue?).

The Cooper lab is at the forefront of NAMS research and have demonstrated that intact protein complexes can be extracted from tissue sections by two complementary techniques: liquid extraction surface analysis (LESA)1,2 and nanospray desorption electrospray ionisation (nano-DESI). Despite these promising results, the underlying mechanisms of extraction of native proteins remain unclear, as do the optimum sampling and analysis conditions. The aim of the project is to address these questions and to further develop these techniques, in addition to a third technique – desorption electrospray ionisation (DESI), for NAMS of a range of tissue types. The research will also involve integration of ion mobility spectrometry techniques with the NAMS techniques to further improve performance. Computational tools for data analysis (protein identification and visualisation of mass spectrometry imaging datasets) will be developed.

References:

  1. Hale, O. J.; Sisley, E. K.; Griffiths, R. L.; Styles, I. B.; Cooper, H. J. J. Am. Soc. Mass Spectrom. 2020, 10.1021/jasms.9b00122.
  2. Griffiths, R. L.; Sisley, E. K.; Lopez-Clavijo, A. F.; Simmonds, A. L.; I.B., S.; Cooper, H. J. Int. J. Mass Spectrom. 2017, 437, 23-29.

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

        Techniques that will be undertaken during the project:

        • Mass spectrometry
        • Liquid extraction surface analysis (LESA)
        • Nanospray desorption electrospray ionisation (Nano-DESI)
        • Desorption electrospray ionisation (DESI)
        • Ion mobility spectrometry (FAIMS, TWIMS)
        • Bioinformatics tools, visualisation software tools

        Contact: Professor Helen Cooper, University of Birmingham