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.
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.
Informal enquiries may be made to email@example.com
HOW TO APPLY
Applications should be made by emailing firstname.lastname@example.org with a CV and a covering letter, 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. We will also require electronic copies of your degree certificates and transcripts.
In addition to the CV and covering letter, please email a completed copy of the NLD BBSRC DTP Studentship Application Details Form (Word document) to email@example.com, noting the additional details that are required for your application which are listed in this form. A blank copy of this form can be found at: https://www.nld-dtp.org.uk/how-apply.
Open to students worldwide
Studentships are funded by the Biotechnology and Biological Sciences Research Council (BBSRC) for 4 years. Funding will cover tuition fees at the UK rate only, a Research Training and Support Grant (RTSG) and stipend. We aim to support the most outstanding applicants from outside the UK and are able to offer a limited number of bursaries that will enable full studentships to be awarded to international applicants. These full studentships will only be awarded to exceptional quality candidates, due to the competitive nature of this scheme.
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