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Conformational dependence of glycan geometry in protein glycosylation: applications for macromolecular refinement in atomic structure determination by X-ray crystallography and electron cryo-microscopy

Department of Chemistry

About the Project

Proteins are composed of 20 individual building blocks, the l-amino acids, linked together by a largely inflexible amide bond. Despite the obvious constraints imposed on polypeptides by the near-planarity of this bond, two other bonds with fewer restrictions offer enough flexibility to give rise to protein secondary structures. Measuring the torsion angles along these bonds can help identify whether a section is α-helical, takes part in a β-strand, or is likely to be unstructured.

At the beginning of the last decade, Tronrud and Karplus from Oregon State University (USA) proposed that the molecular geometry of the protein’s backbone (N-Cα-C=N-Cα-C…) had a strong dependence on the overall conformation of the polypeptide (Acta Cryst D67(8):699–706), which, as we know, can be expressed in terms of torsion angles. This result was applied to macromolecular crystallographic refinement, where prior knowledge of the geometry of chemical bonds can supplement incomplete experimental information in order to construct a better atomic model.

Glycans, which are of great biological significance as protein glycosylation, are formed by linking and branching monosaccharides through glycosidic bonds. In glycosylated proteins, glycans are also covalently attached to one side-chain in a small subset of amino acids. These bonds are highly flexible, and have been shown to adopt different conformations in a range of situations.

By analysing the molecular geometry of glycans - bond lengths, angles and torsion angles – in all available atomic structures of glycoproteins (to be downloaded from the Protein Data Bank), you will be producing detailed information that can inform the process of macromolecular refinement when the experimental data are not resolute to the point of ascertaining atomic positions. The results will not only be useful for X-ray crystallography, but most importantly for electron cryo-microscopy (Cryo-EM), the 2017 Nobel prize-winning technique that is currently producing most structural data of viral glycoproteins, including those in SARS-CoV-2. The resulting conformation-dependent library will be distributed by both Collaborative Computational Projects CCP4 (macromolecular crystallography) and CCP-EM (cryoEM). The outcome from the torsional analysis will also be helpful as a validation tool, and will be integrated into our successful Privateer software tool (Nat Struct & Mol Biol 22(11):833-834).

Depending on the successful candidate’s qualifications, taking an ‘Introduction to Python programming’ course might be desirable. This runs regularly in the Department of Chemistry at the University of York, and familiarises the students with programmatic access to public databases, which is one the features we expect to incorporate to our software. Also, should the candidate not come from a structural biology background, a list of relevant modules from our undergraduate courses will be identified in order to bring the candidate up to speed. The project will also provide externally-funded opportunities for teaching and training in specialised structural biology workshops in the UK and overseas through the York-exclusive Hartshorn-Jones fund (which may cover both training and purchases of hardware and software), Collaborative Computational Projects for macromolecular crystallography (CCP4) and electron cryo-microscopy (CCP-EM).

All Chemistry research students have access to our innovative Doctoral Training in Chemistry (iDTC): cohort-based training to support the development of scientific, transferable and employability skills:

The Department of Chemistry holds an Athena SWAN Gold Award and is committed to supporting equality and diversity for all staff and students. The Department strives to provide a working environment which allows all staff and students to contribute fully, to flourish, and to excel:

You should hold or expect to achieve the equivalent of at least a UK upper second class degree in Chemistry or a related subject. Please check the entry requirements for your country:

For more information about the project, click on the supervisor’s name above to email the supervisor. For more information about the application process or funding, please click on email institution

Funding Notes

This project is available to students from any country who can fund their own studies.

The Department of Chemistry at the University of York is pleased to offer Wild Fund Scholarships. Applications are welcomed from those who meet the PhD entry criteria from any country outside the UK. Scholarships will be awarded on supervisor support, academic merit, country of origin, expressed financial need and departmental strategy. For further details and deadlines, please see our website: View Website

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