Conformation-sensitive mass spectrometry: developing HDX and FPOP-MS approaches with high temporal and spatial resolution together with computational modelling

High-resolution structural methods such as x-ray crystallography, NMR and now increasingly also EM are making important contributions to our understanding of biomolecular structure and function. Determining how proteins interact with other molecules is key in understanding most biological process, for the development of novel therapeutics and for biotechnology. Yet many protein structures are highly dynamic and heterogeneous, making it difficult to capture their complete conformational behaviour and assembly pathways using such high-resolution structural snapshots.

Structural proteomics methods which take advantage of recent, cutting-edge mass spectrometry approaches are now coming into their own, as they can map out the conformational space of structurally dynamic, even disordered and natively unfolded proteins, as well as characterizing heterogeneous assembly pathways, e.g. in amyloid aggregation. While most “traditional” techniques will highlight either the most dominant (stable) form, or an average of all states, structural MS is uniquely powerful in that it can characterize whole ensembles in an unbiased fashion.

This project involves the development and application of cutting-edge structural MS methods, in particular hydrogen-deuterium exchange (HDX) and hydroxyl radical footprinting (fast photo-chemical oxidation of proteins, FPOP). You will develop novel approaches which aim to increase the temporal and spatial resolution of the labelling and take full advantage of the combination of data form both. You will also work with challenging, high-profile targets such as oligomeric amyloid protein (believed to be the toxic form) as well as membrane proteins. In combination with computational modelling, we can build structural models of complex and dynamic systems.

You will work under the supervision of Prof Frank Sobott and Dr Anton Calabrese, in collaboration with Dr Emanuele Paci (Leeds, computational modelling) in Leeds’ world class Biomolecular MS laboratory which houses 7 instruments dedicated to structural mass spectrometry. You will receive training in structural mass spectrometry methodologies as well as computational data interpretation and modelling, a highly sought after skill for the characterization of protein structure and biotherapeutics, and push the limits of current structural mass spectrometry capabilities.

You are highly motivated, can work independently and have good communication skills. You have a degree in Chemistry, Biochemistry, Physics or a related subject. Both UK and EU-based students can apply.