Dr Jim Warwicker, Prof P Barran
No more applications being accepted
Competition Funded PhD Project (European/UK Students Only)
About the Project
University of Manchester Supervisor: Dr Jim Warwicker, Dr Perdita Barran. A*STAR Supervisor: Chandra Verma (BII).
Intrinsically disordered proteins (IDPs) are conveniently recognised by sequence characteristics, as a balance between charge and hydrophobicity [1]. Further, charge plays a major role in modulating function of IDPs, for example post-translational modification (PTM) by phosphorylation is highly enriched in disordered regions. Our aim is to improve molecular understanding of charge coupling to IDP conformation and function through computational modelling. In some cases specific charge modification will mediate interactions and biological specificity, in others function may be mediated through charge modulation of conformational sampling, which will in turn alter the accessibility of functionally relevant sites within an IDP. Thus, we need to couple proteomic and other data on function and functional sites with conformational analysis. Bioinformatically, there are a multitude of data resources available, from simple proteome sequences to gene ontology (GO) and PTM data. Molecular simulations will provide the tools for conformational sampling, and coarse-graining methods will be tested for their ability to enable fast calculations suitable for web-based prediction. Empirical models for charge interactions have provided a valuable framework for understanding pH-dependence and other charge effects in natively folded proteins, and similar models will be superposed on the simulation-based conformational sampling to give an additional measure of the energetics.
This project will draw together bioinformatics [2] and simulation [3] strands that Manchester and Singapore groups have applied in the recent past, to make a combined model for the research community. We know that charge is important in establishing IDPs, we don’t yet know how charge modulation refines the functional properties of IDPs, so that this project targets an important facet of a major class of proteins. It will benefit from a collaborative environment that includes parallel work from mass spectrometric analysis of charge effects on protein conformation [4].
Funding Notes
This project is available to UK/EU candidates. Funding covers fees (UK/EU rate) and stipend for four years. Overseas candidates can apply providing they can pay the difference in fees and are from an eligible country. Candidates will be required to split their time between Manchester and Singapore, as outlined on www.manchester.ac.uk/singaporeastar.
Applications should be submitted online and candidates should make direct contact with the Manchester supervisor to discuss their application directly. Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.
References
[1] Uversky VN. Intrinsically disordered proteins from A to Z. Int J Biochem Cell Biol (2011) 43:1090.
[2] Mittag T et al. Protein dynamics and conformational disorder in molecular recognition. J Mol Recognit (2010) 23:105.
[3] Cawley A and Warwicker J. eIF4E-binding protein regulation of mRNAs with differential 5’-UTR secondary structure: a polyelectrostatic model for a component of protein-mRNA interactions. Nucleic Acids Res (2015) 40:76666.
[4] Kannan S et al. Long range recognition and selection in IDPs: the interactions of the C-terminus of p53. Sci Rep (2016) 6:23750.
[5] Jhingree JR et al. Charge mediated compaction and rearrangement of gas-phase proteins: a case study considering two proteins at opposing ends of the structure-disorder continuum. J Am Soc Mass Spectrom (2017) 28:1450 (2017).