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

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 CCP-EM 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). 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. An ensemble of search models may better match the set of conformational possibilities contributing to the Cryo-EM map. The successful applicant will also therefore test this idea and examine and compare alternative means to generate structure ensembles.

The project offers the student training in cutting-edge bioinformatics and structural biology methods and interaction with the leading consortia in the area, CCP4 and CCP-EM.

The project is suited to a student with at least a good B.Sc. Upper Second in Biological or Life Sciences, or possibly in computational subjects.