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The lipid connection: Determinants of dynamic protein structure and interactions in the membrane environment investigated by structural mass spectrometry and computational modelling


Project Description

This PhD project uses a combination of innovative experimental and computational strategies, with the main emphasis on structural proteomics / mass spectrometry and modelling. We study a range of membrane protein systems that are involved in antibiotic resistance, cancer and heart disease, and how the lipid environment determines their conformational properties and interactions.
The methods we use are based on mass spectrometry (MS), using novel approaches such as native MS combined with ion mobility which gives us a view on the global protein structure, complex size and stoichiometry, interacting lipids and ligand binding (even in heterogeneous samples) and their conformational as well as (de-)stabilizing effects on the structure. Hydrogen-deuterium exchange (HDX) and Fast photochemical oxidation of proteins (FPOP) are two complementary approaches which can provide unprecedented detail of exposed and interacting protein surface areas, even in a membrane-like detergent or lipid environment, by using covalent labels (deuterium and radical hydroxyl groups, respectively) detected by MS after proteolytic digestion and liquid chromatography separation of the resulting peptides. These data are then used to build structural/molecular models of the proteins and their complexes with the help of molecular dynamics (MD) and docking approaches. MD simulation methodologies enable us to follow the dynamics of proteins and to unravel details of their interactions with their lipid environment.
A novel MS platform based on a ultra-high mass range Orbitrap which was recently acquired in the MS facility and is currently almost unique in the UK, will transform our ability to study lipid interactions of membrane proteins. Leeds also hosts a state-of-the-art High Performance Computer Cluster, which will be used for the proposed computational studies. Taken together with electron microscopy, where Leeds has recently seen major investment in the Astbury Biostructure Laboratory (ABSL) creating a world-class facility for the study of dynamic and complex biomolecular structures, this project utilizes our unique capabilities to further our understanding of medically important protein systems. The candidate will have unique opportunities to acquire a broad range of competencies that include advanced experimental and computational techniques, crucial for a future leader in the field of biomolecular structure particularly of membrane proteins. The project will be supervised by Prof Sobott, Dr Muench and Dr Kalli, experienced scientists in structural, cellular and computational biology methods. Recent PhD graduates from these groups have published first author papers in high quality journals and progressed to research positions in academic or industrial laboratories.

Funding Notes

Project is eligible for funding under the FBS Faculty Studentships scheme. Successful candidates will receive a PhD studentship for 4 years, covering fees at UK/EU level and stipend at research council level (£14,777 for 2018-19).
Candidates should have, or be expecting, a 2.1 or above at undergraduate level in a relevant field. If English is not your first language, you will also be required to meet our language entry requirements. The PhD is to start in Oct 2018.
Please apply online here View Website Include project title and supervisor name, and upload a CV and transcripts.

References

FS:
Konijnenberg, A., Ranica, S., Narkiewicz, J., Legname, G., Grandori, R., Sobott*, F., Natalello*, A. (2016) Opposite Structural Effects of Epigallocatechin-3-gallate and Dopamine Binding to α-Synuclein. Anal Chem. 88, 8468.
Konijnenberg, A., Sobott, F. (2015) Bouncing off the walls: excited protein complexes tell their story. Chem. Biol 22, 583.
Lermyte, F., Sobott, F. (2015) Electron transfer dissociation provides higher-order structural information of native and partially unfolded protein complexes. Proteomics, 15, 2813.
Konijnenberg, A., Yilmaz, D., Ingólfsson, H.I., Dimitrova, A., Marrink, S.J., Lid, Z., Vénien-Bryan, C., Sobott*, F., Koçer*, A. (2014) Global structural changes of an ion channel during its gating are followed by ion mobility mass spectrometry.
PNAS, 111, 17170. (* co-corresponding authors)

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