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Unravelling the conformational dynamics of membrane proteins within a lipid environment

Project Description

This studentship will enable a new multidisciplinary strategy for elucidating the structural dynamics of membrane proteins in lipid context. Membrane proteins are embedded into a heterogeneous mixture of lipids that affects their structure, dynamics and function. Characterising protein-lipid interactions is a challenge and only a small portion of membrane protein structures is available in the relevant databases. Moreover, we know frustrating little about membrane protein dynamics, thus hindering a detailed understanding of their mechanism of action.

With this project, we will bring together a new combination of mass spectrometry (MS)-based approaches – hydrogen-deuterium exchange (HDX)-MS, and cyclic ion mobility (IM)-MS – with single molecule atomic force microscopy, AFM. HDX-MS will probe lipid-induced protein dynamics at peptide-level resolution, cyclic IM-MS will uncover co-populated states and unfolding pathways and AFM will elucidate conformational pathways and differences in (un)folding pathways. The novelty lies in combining these techniques for probing lipid-modulated structural changes in membrane proteins; such changes are largely inaccessible by the existing approaches in isolation. We will establish our approach using exemplar membrane proteins for which high-resolution structures are available. We will examine how the surrounding lipid environment affects protein dynamics using nanodiscs. The nanodisc technology allows for reconstitution of membrane proteins into a native-like environment of tuneable lipid composition. Overall, the innovative integration of these tools will enable a new strategy for probing membrane protein dynamics and can readily be extended to any membrane protein of interest.

The student will be integrated into two dynamic and highly productive labs at King’s College London and an academic partner (Waters). They will be trained in expressing, purifying and reconstituting membrane proteins in nanodiscs as well as performing HDX-MS, IM-MS and AFM experiments. The student will spend time working at Waters Headquarters in Manchester where they will be part of vibrant industrial environment of a leading manufacturers of mass spectrometers worldwide.


Applications must be complete, including both references, by 24th January 2020

Funding Notes

Fully funded places, subject to UKRI eligibility, for UK/EU students including home (UK) tuition fees and a tax-free stipend in the region of £17,009.


1) Martens C, Shekhar M, Lau A, Tajkorshid E, Politis A. Integrating Hydrogen-Deuterium exchange mass spectrometry with Molecular Dynamics simulations to probe lipid-modulated conformational changes in membrane proteins. Nature Protocols, Accepted, In press.
2) Martens C, Shekhar M, Borysik AJ, Lau AM, Reading E, Tajkorshid E, Booth PJ, Politis A, (2018) Direct protein-lipid interactions shape the conformational landscape of secondary transporters. Nature Communications, 9;415., 2018
3) Hansen KJ, Lau AM, Giles K, McDonnell J, Sutton B, Politis A. A mass spectrometry-based modelling workflow for accurate prediction of IgG antibody conformations in the gas phase. Angewandte Chemie, 57, 1-7, 2018
4) Infante, E*.; Stannard, A.*; Board, S.J.; Rico-Lastres, P.; Rostkova, E.; Beedle, A.E.M.; Lezamiz, A.; Wang, Y.J.; Gulaidi Breen, S.; Panagaki, F.; Sundar Rajan, V.; Shanahan, C.; Roca-Cusachs, P.; Garcia-Manyes, S. The mechanical stability of proteins regulates their translocation rate into the cell nucleus. Nature Physics 2019.
5) Beedle, A.E.M.; Mora, M.; Davis, C; Brijnders, B.; Stirnemann, G.; Garcia-Manyes, S. Forcing the reversibility of a mechanochemical reaction. Nature Communications 2018; 9(1):3155.

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