Adenosine tri-phosphate (ATP) is the main metabolite for cellular energy production playing a role in many biological processes. Recently, it has been suggested that ATP has evolved to maintain cell stability, which is why ATP occurs at mM concentrations in cellular environments even though mM concentrations are required for metabolism. Within cells, proteins containing intrinsically disordered regions (IDRs) often occur in densely packed macromolecular environments, which function as membraneless orgranelles (MLOs). ATP is likely required to maintain MLO stability and prevent irreversible association of IDR proteins into amyloids, which lead to diseased states in cells. Indeed, lower concentrations of ATP are found in diseased versus healthy cells. The dramatic effects of ATP on protein assembly in vivo has led us and others to investigate the solubilizing properties of ATP for applications in manufacturing biopharmaceuticals. Indeed, ATP is effective at suppressing protein aggregation; aggregates are strictly regulated in biopharmaceutical production due to harmful effects when administered to patients. In addition, ATP can be used for controlling protein phase behaviour, which opens up applications in downstream purification and for protein structure determination by crystallography. The broad range of effects suggests ATP binds non-specifically with many, if not all, proteins and the binding has significant consequences for protein self-assembly. The overall goal is to elucidate the impact of ATP on protein solution behaviour using model systems. Due to the weak and transient nature of the underpinning biomolecular interactions, solving the problem requires complementing experimental studies with computational modelling tools. The PhD studentship is split equally between working at University of Manchester (Years 1 and 4) and the Bioinformatics Institute in Singapore (Years 2 and 3). The experimental studies will be carried out at Manchester, which provides access to a suite of high-resolution biophysical characterization tools. ATP binding to proteins will be characterized using isothermal titration calorimetry (ITC), nuclear magnetic resonance spectroscopy (NMR), and crystallography, while protein self-assembly and phase behaviour will be studied using light scattering technologies coupled in some cases with size exclusion chromatography (SEC). At BII, simulations will be developed for studying ATP binding to proteins and for determining how the binding alters protein-protein interactions. The simulations will unravel the molecular determinants of how ATP alters protein self-assembly and aggregation. Taken together the project provides training in biophysical characterization tools and modelling which are essential in biopharmaceuticals research and development and are emerging tools being applied in cell biology.
Entry Requirements:
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 a related subject area.
Many of our students have also undertaken a master's degree, although this is not compulsory.
International applicant eligibility requirements: Some restrictions apply to applicants from certain Asian countries. In general, students from Europe, the Americas, Africa, Australia, New Zealand, Korea and Japan are eligible to apply for the programme. Unfortunately, we cannot accept applications from south-east Asian countries such as Singapore, China and Malaysia.
International applicants must ensure they meet the academic eligibility criteria (including English language) as outlined before contacting potential supervisors to express an interest in their project.
How to Apply
To be considered for this project you MUST submit a formal online application form - full details on how to apply can be found on the A*STAR PhD website https://www.bmh.manchester.ac.uk/study/research/astar/
Equality, Diversity and Inclusion
Equality, diversity and inclusion is fundamental to the success of The University of Manchester, and is at the heart of all of our activities. The full Equality, diversity and inclusion statement can be found on the website https://www.bmh.manchester.ac.uk/study/research/apply/equality-diversity-inclusion/
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