Imperial College London Featured PhD Programmes
The University of Manchester Featured PhD Programmes
Norwich Research Park Featured PhD Programmes
FindA University Ltd Featured PhD Programmes
Cardiff University Featured PhD Programmes

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

Project Description

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 -helical, takes part in a -strand, or is likely to be unstructured.

At the beginning of this decade, Tronrud and Karplus from Oregon State University (USA) proposed that the molecular geometry of the protein’s backbone (N-C-C=N-C-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 almost instantly to macromolecular crystallographic refinement, where detailed 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 frequently 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 (see figure on the right for an example).

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 prove precious to 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 (cryoEM), the 2017 Nobel prize-winning technique that is currently producing most structural data of viral glycoproteins. Although it is expected to improve in forthcoming years thanks to the technological advances in electron sources, direct-electron detectors and image-processing software, the current average resolution of a cryoEM experiment more than justifies the need for the best geometric information we can provide.

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).

All research students follow our innovative Doctoral Training in Chemistry (iDTC): cohort-based training to support the development of scientific, transferable and employability skills. All research students take the core training package which provides both a grounding in the skills required for their research, and transferable skills to enhance employability opportunities following graduation. Core training is progressive and takes place at appropriate points throughout a student’s higher degree programme, with the majority of training taking place in Year 1. In conjunction with the Core training, students, in consultation with their supervisor(s), select training related to the area of their research.

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 Collaborative Computational Projects for macromolecular crystallography (CCP4) and electron cryo-microscopy (CCP-EM).

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. Chemistry at York was the first academic department in the UK to receive the Athena SWAN Gold award, first attained in 2007 and then renewed in October 2010 and in April 2015.

Funding Notes

This project is open to students who can fund their own studies or who have been awarded a scholarship separate from this project. The Chemistry Department at York is pleased to offer Wild Fund Scholarships to those from countries outside the UK. Wild Fund Scholarships offer up to full tuition fees for those from countries from outside the European Union. EU students may also be offered £6,000 per year towards living costs. For further information see: View Website

Related Subjects

How good is research at University of York in Chemistry?

FTE Category A staff submitted: 47.06

Research output data provided by the Research Excellence Framework (REF)

Click here to see the results for all UK universities

Email Now

Insert previous message below for editing? 
You haven’t included a message. Providing a specific message means universities will take your enquiry more seriously and helps them provide the information you need.
Why not add a message here
* required field
Send a copy to me for my own records.

Your enquiry has been emailed successfully

FindAPhD. Copyright 2005-2019
All rights reserved.