We encourage applications for our partner studentships with research organisation at the Oxford Harwell Campus (Diamond Light Source, ISIS Neutron and Muon Source, STFC Central Laser Facility, the Research Complex at Harwell and the Rosalind Franklin Institute), which support research undertaken under the joint supervision of researchers based at Harwell and the University of Oxford or Oxford Brookes University. These studentships may be of particular interest to students with interests in areas such as bioimaging, structural biology, spectroscopy, biophysics, data science and molecular dynamics.
We welcome applications from students who hold, or are on target to achieve a first-class or strong upper second-class undergraduate degree (or equivalent international qualifications), as a minimum, in a relevant academic subject. Up to 38 studentships are available for UK and EU students for the forthcoming academic year supported by the BBSRC and the partnership (BBSRC eligibility criteria apply).
Candidates interested in working with Harwell research organisations are encouraged to apply for general entry to the Oxford Interdisciplinary Bioscience DTP and to state in their application that they wish to be considered for a Harwell studentship. Their personal statement should include an explanation of their interest in working with one or more Harwell research organisations.
If you wish to apply to one of these studentships please contact us at email@example.com. The deadline for Harwell studentship applications is 12 noon, Friday 24th January.
Some examples of DPhil projects available at Harwell include:
Engineering proteins for time resolved studies (Rosalind Franklin Institute and the Department of Chemistry, Oxford)
Enzymes catalyse the array of reactions that drive life; the exploitation of enzymes is at the core of the biotechnology industry. Yet our understanding of how most enzymes work is limited. X-ray free electron lasers (XFELs) hold the promise of studying enzyme reactions on the nanosecond time scale, enabling individual steps in catalysis to be studied. This knowledge would revolutionise the understanding of enzyme mechanism, so enabling new applications in biotechnology.
XFEL analysis of intermediates requires uniform triggering and harmonisation of reactions. Few enzyme reactions are, however, suitable for XFEL analysis; these mostly involve electron transfer processes that can be controlled by flashing of a laser. It is possible to chemically modify substrates such that they are inactive until they are flashed by a laser. There are challenges with the substrate photo-caging approach. The synthesis of caged substrates is non trivial, the chemistry required for one system is usually not applicable to another, and the caged substrate may not bind to the enzyme. Rapid mixing of the enzyme and substrate is an alternative, but this usually not optimal leading to difficulties in synchronising reactions in a crystal.
This project concerned the development of methods for enzyme photo-caging. In principle this is a general method, since all almost all enzyme catalysis involves a limited number of amino acids. In vitro protein synthesis methods were used to produce enzymes with a caged amino acid(s) at the active site resulting in an inhibited enzyme-substrate complex suitable for crystallisation. The illumination of the sample with a laser will remove the cage from the protein and thus initiate catalysis. The project provided training in cutting edge enzymology and structural biology, within the context of understanding the roles of enzymes in biomedicinally relevant processes, such as antibiotic resistance.
Post-Translational Mutagenesis: a New Way of Engineering Biology (Rosalind Franklin Institute and the Department of Chemistry, Oxford)
Natural post-translational modifications (PTMs) to proteins expand the chemical groups available to proteins, modulating both structure and function. They can be critical in a range of pathways with diverse biological effects. The ability to expand post-translational functional group diversity in an unbounded manner could therefore, in principle, allow exploration and understanding of even more diverse effects in modulating biological function. Known, natural PTMs feature bonds to heteroatoms (non-carbon) made at the g (Cys Sg, Thr Og, Ser Og) or w (Lys Nw, Tyr Ow) positions of sidechains. Yet, one of the central features of living ‘organic’ matter is that it exploits carbon’s ability as an element to catenate (typically through C(sp3)–C(sp3) bond formation) — providing one of nature’s most important structural motifs. As all amino acid side-chains contain this C–C bond, mastering its construction on proteins could allow free-ranging structural alteration of residues in proteins (both natural and unnatural) that could be considered a near unlimited form of synthetic biology and a new form of ‘chemical mutagenesis’. [Science 2016, 354, 597];[Nature 2018, 563, 235]
In principle, carbon(sp3)-carbon(sp3) disconnections at the b,g C–C bond in side-chains would allow the chemical installation of not only natural amino acid residues but also PTM variants and a wide range of unnatural amino acids. We will explore whether such amino acid residues can be introduced in a site-selective manner genetically, biosynthetically or chemically.
A range of radicals R• can allow the design of amino acids in peptides and proteins with site- and regio- selectivity. Mechanistic analysis should allow us to discover conditions for suitable ‘quenching’ of radical intermediates. Radicals should also be stable too to the presence of charged or polar protic (e.g. OH, NH) functionality in Biology. The use of sidechain reagents should therefore prove possible without protection, testing not only exquisite chemoselectivity but also compatibility with common biological groups. This could allow Biology to be explored in an unique manner allowing even the re-programming and examination of Biology in living systems.