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Working at the intersection of protein bioinformatics and structural biology: exploiting protein structural ensembles to facilitate structure solution from X-ray crystallography and cryo-EM

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  • Full or part time
    Prof D Rigden
    Dr O Davies
    Dr R Keegan
  • Application Deadline
    No more applications being accepted
  • Competition Funded PhD Project (European/UK Students Only)
    Competition Funded PhD Project (European/UK Students Only)

Project Description

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 projects 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.

Finally, the project also offers the applicant an internship in a crystallographic lab with exposure to practical methods and, in particular, the importance of unconventional approaches to solve difficult cases. Bridging three established and productive research environments the student will be offered a range of training opportunities as well as networking opportunities with the premier UK consortia for structural biology software.

HOW TO APPLY
Applications should be made by emailing [Email Address Removed] with a CV (including contact details of at least two academic (or other relevant) referees), and a covering letter – clearly stating your first choice project, and optionally 2nd and 3rd ranked projects, as well as including whatever additional information you feel is pertinent to your application; you may wish to indicate, for example, why you are particularly interested in the selected project(s) and at the selected University. Applications not meeting these criteria will be rejected.
In addition to the CV and covering letter, please email a completed copy of the Additional Details Form (Word document) to [Email Address Removed]. A blank copy of this form can be found at: https://www.nld-dtp.org.uk/how-apply.

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

Funding Notes

This is a 4 year BBSRC studentship under the Newcastle-Liverpool-Durham DTP. The successful applicant will receive research costs, tuition fees and stipend (£15,009 for 2019-20). The PhD will start in October 2020. Applicants should have, or be expecting to receive, a 2.1 Hons degree (or equivalent) in a relevant subject. EU candidates must have been resident in the UK for 3 years in order to receive full support. Please note, there are 2 stages to the application process.

References

Extending the scope of coiled-coil crystal structure solution by AMPLE through improved ab initio modelling. Acta Cryst D 2019, submitted
Molecular replacement using structure predictions from databases. Acta Cryst D 2019, in press

SIMBAD: a sequence-independent molecular-replacement pipeline. Acta Cryst D 2018 Jul 1;74(Pt 7):595-605.

Ensembles generated from crystal structures of single distant homologues solve challenging molecular-replacement cases in AMPLE. Acta Cryst D2018 Mar 1;74(Pt 3):183-193.

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.

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.

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.

Structural basis of meiotic chromosome synapsis through SYCP1 self-assembly. Nature Structural & Molecular Biology. 2018 25, 557-569.

Structural basis of meiotic telomere attachment to the nuclear envelope by MAJIN-TERB2-TERB1. Nature Communications. 2018 9,
5355.

A molecular model for self-assembly of the synaptonemal complex protein SYCE3. Journal of Biological Chemistry. 2019, 294 (23), 9260-9275.



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