This project is one of a number that are in competition for funding from the South West Biosciences Doctoral Training Partnership (SWBio DTP). The DTP offers an interdisciplinary research training programme delivered by a consortium comprising the Universities of Bath, Bristol and Exeter, Cardiff University and Rothamsted Research, alongside six regional associate partners: Marine Biological Association, Plymouth Marine Laboratory, Swansea University, UCB Pharma, University of the West of England and SETsquared Bristol. The partnership has a strong track record in advancing knowledge through high quality research and teaching, in collaboration with industry and government. For more information about the DTP, see https://www.swbio.ac.uk/
Studentships are available for entry in September/October 2020.
All SWBio DTP projects will follow a structured 4-year PhD model, combining traditional project-focussed studies with a taught first year which includes directed rotation projects.
Overview of this PhD project:
Prof Alison Walker, Department of Physics (University of Bath) https://researchportal.bath.ac.uk/en/persons/alison-walker
Dr Marc van der Kamp (University of Bristol) http://www.bris.ac.uk/biochemistry/people/marc-w-van-der-kamp/index.html
Dr Christopher Pudney (University of Bath) https://researchportal.bath.ac.uk/en/persons/christopher-pudney
The relationship between the structure of a protein and its function is vital to understanding how molecules give rise to biological effects. We will study structural adaptation of extremophilic enzymes to their ambient temperature through their flexibility and dynamics. Experimental structure determination is time-consuming and costly so is not practical for the many variants of a protein under optimization, nor is ab initio modelling of protein structure yet tractable. This project will develop a modelling tool combining two complementary modelling methods developed at Bath Physics and Bristol Biochemistry. The tool will be used by an experimental group in Bath Biology and Biochemistry who develop experimental approaches to rapidly test proteins for their native function based on accurate detection of their dynamics and flexibility, termed the dynamic profile. There are industrial applications and potential for use in a clinical setting.
The dynamics and flexibility of a protein are key to its function: many enzymes undergo substantial, reversible conformational changes during chemical operation. We will use simulation methods taking as input a protein structure, obtained through protein crystallography, and explore its motions from small local rearrangements such as side chain reorientations, to large domain motions such as hinge motion. This project combines a code that undertakes geometric simulations of intrinsic flexible motion in enzymes with enhanced sampling molecular dynamics on these structures that focus on picosecond timescales. Molecular dynamics is used to study how effective the enzyme is as a catalyst.
Enzyme stability and flexibility in different conditions is a crucial aspect for enzyme activity and durability, both for extremophilic life-forms as well as biocatalysts for industrial biotechnology. The rigidity of enzyme structures needs to be finely balanced to allow for sufficient stability (e.g. at high temperature, high salt concentration) as well as maintaining the flexibility required for activity (turnover). The project will examine structural adaptations that can change the rigidity of enzyme structures, e.g. saltbridges, hydrogen bonding and hydrophobic interactions. Code development will take place to make improvements to its description of the physics and to become more user friendly.
The student will acquire an in-depth knowledge and training in enzyme structure and function, interpretation of experimental measurements, and programming skills and techniques using C++ and Python.
Applicants must have obtained, or be about to obtain, a First or Upper Second Class UK Honours degree, or the equivalent qualifications gained outside the UK, in any of physics, chemistry, biology, or natural sciences and have a strong interest in coding.
How to apply:
Applications should be submitted on the University of Bath’s online application form for a PhD in Biosciences: https://samis.bath.ac.uk/urd/sits.urd/run/siw_ipp_lgn.login?process=siw_ipp_app&code1=RDUBB-DT01&code2=0004
Please ensure that you quote the supervisor’s name and project title in the ‘Your research interests’ section. You may apply for more than one project if you wish but you should submit a separate personal statement relevant to each one
More information about applying for a PhD at Bath may be found on our website: https://www.bath.ac.uk/guides/how-to-apply-for-doctoral-study/