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Exploring structural ensembles to enhance unconventional Molecular Replacement and facilitate Cryo-EM map interpretation

   Faculty of Health and Life Science

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  Prof D Rigden, Dr R Keegan  No more applications being accepted  Self-Funded PhD Students Only

Liverpool United Kingdom Biochemistry

About the Project

Applications will be reviewed until a suitable candidate is found.

Self funded PhD students only.

Structural biology contributes enormously to advances across all areas of biology. X-ray crystallography is the major structure determination workhorse but cryo-EM studies are increasingly popular and powerful. These routes both involve significant computation and are served by the CCP4 and CCPEM software suites respectively. This project involves working at the intersection of structural bioinformatics and structural biology and will result in improvements to both suites.

In the area of protein crystallography the project will improve methods for unconventional Molecular Replacement (MR). Solving the ‘phase problem’ is essential in crystallography to allow calculation of the first, approximate electron density maps, and MR is the predominant method for solution. MR can be relatively routine when a highly similar structure to the unknown target is already available. When this is not the case unconventional methods, for example involving ab initio modelling or structural fragments, can be employed. Our recent work in the area consistently shows that structural ensembles - superpositions of different proteins, or conformational states of the same protein - outperform single structures in unconventional MR. The successful applicant will explore and benchmark different methods to explore protein conformational space and thereby generate ensemble search models. These procedures will accelerate protein crystal structure solution in difficult cases by making better use of related structures in the PDB and new-generation models coming from advanced methods such as Google AlphaFold deposited in databases. The novel methods will be implemented in new modules of our well-known AMPLE pipeline for unconventional MR.

The cryo-EM part of the project involves fitting of domains to medium resolution maps. Where resolution does not allow for direct chain tracing models can be built piecemeal from placing of existing structures or domains. There is good reason to think that structural ensembles will be more easily placed than single structures, especially where the local resolution of the map at the surface is worse. The successful applicant will also therefore test this idea and examine and compare alternative means to generate structure ensembles.

Informal enquiries may be made to Professor Rigden: [Email Address Removed]

To apply please send a CV and covering letter (plus references if available) to Professor Rigden: [Email Address Removed]'

Funding Notes

The project is open to both European/UK and International students. It is UNFUNDED and applicants are encouraged to contact the Principal Supervisor directly to discuss their application and the project.
Assistance will be given to applications who are applying to international funding schemes.
The successful applicant will be expected to provide the funding for tuition fees and living expenses. Research costs will be covered by the supervisor.
Details of costs can be found on the University website: https://www.liverpool.ac.uk/study/postgraduate-taught/finance/#living-expenses


1. Redeployment of automated MrBUMP search model identification for map fitting in CryoEM. Acta Cryst D 2020,
2. Maturation of the functional mouse CRES amyloid from globular form. Proc Natl Acad Sci U S A. 2020 117:16363-16372.
3. Molecular replacement using structure predictions from databases. Acta Cryst D 2019, 75, 1051-1062.
4. SIMBAD: a sequence-independent molecular-replacement pipeline. Acta Cryst D 2018 Jul 1;74(Pt 7):595-605.
5. Ensembles generated from crystal structures of single distant homologues solve challenging molecular-replacement cases in AMPLE. Acta Cryst D 2018 Mar 1;74(Pt 3):183-193.
6. Recent developments in MrBUMP: better search-model preparation, graphical interaction with search models, and solution improvement and assessment. Acta Cryst D 2018 Mar 1;74(Pt 3):167-182.
7. Residue contacts predicted by evolutionary covariance extend the application of ab initio molecular replacement to larger and more challenging protein folds. IUCrJ. 2016 Jun 15;3(Pt 4):259-70.
8. AMPLE: a cluster-and-truncate approach to solve the crystal structures of small proteins using rapidly computed ab initio models. Acta Cryst D 2012 Dec;68(Pt 12):1622-31.
9. A practical overview of molecular replacement: Clostridioides difficile PilA1, a difficult case study. Acta Crystallogr D Struct Biol. 2020 76:261-271.
10. Structure and assembly of the S-layer determine virulence in C. difficile. Under review, Nature.
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