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PDRA, Mass Spectrometric Protein Structure Analysis

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The Rosalind Franklin Institute (the Franklin) is a new national Research Centre, funded by the UK government through UK Research and Innovation, dedicated to bringing about transformative changes in life science through interdisciplinary research and technology. The Biological Mass Spectrometry theme focuses on the development of new instrumentation for mass spectrometric imaging (MSI) allowing the visualisation of molecular distributions at subcellular level and the de-novo structure elucidation of chemical species detected by MSI techniques. The ultimate goal of the Theme is to understand the working mechanism of molecular interaction networks in health and disease and define novel diagnostic and prognostic targets for next generation healthcare.

The project will focus on the detection of different macromolecular conformers present in tissues using a variety of MSI approaches. To facilitate the rapid adoption and application of the tandem TIMS-TOF-FT-ICR for the imaging of the intact proteins, it is proposed to a) perform benchmarking experiments of current capabilities on existing instruments; b) generate training and validation data (on existing instruments) for the development of data analysis workflows and c) interrogate the effects of the new TIMS device on protein structure during visits to our industrial partner's laboratories in Germany during the initial build phase.

Benchmarking experiments will comprise the use of protein reference standards and thin tissue sections together with existing atmospheric pressure ambient ionization techniques, specifically desorption electrospray ionization and liquid extraction surface analysis as a proxy for the piezoelectric droplet-on-demand device. Experiments will be performed on high resolution mass spectrometers within the laboratories of the project partners. Generation of training and validation data will be undertaken on FT-ICR mass spectrometers currently available in project partners’ laboratories. In addition, datasets will be generated by use of alternative ion mobility spectrometry technology (high field asymmetric waveform ion mobility spectrometry, FAIMS) coupled with orbitrap mass spectrometry, as this approach has been demonstrated to give the greatest depth of proteome coverage for intact proteins to date. Fragmentation data will be generated using a range of tandem mass spectrometry techniques (ECD, ETD, CID) and will form the basis of WP6.

Ion conformational studies, that is interrogation of the effect of TIMS on protein structure, will be performed on TIMS-TOF mass spectrometers (and the tandem TIMS-TOF-FT-ICR as it is built) in the Bruker laboratories in Bremen. These experiments are crucial for application of the new instrument to elucidation of protein structure.

The project is a collaboration with Member Institutions including University of Oxford, University of Birmingham, University of Edinburgh and Imperial College London. The postholder is expected to be hosted at Birmingham. The post reports to the Franklin’s Theme Leads for Biological Mass Spectrometry (Profs Josephine Bunch and Zoltan Takats), and will also work with MS leads of the Franklin Member Institutions.

This is essentially a post-doctoral research associate role, however we may be able to consider senior post-doctoral research associates, depending on their skills and experience. The duration of the post is 18 months' fixed-term contract.

Responsibilities

You will:

• Embrace the primary project of the role, namely developing MSI approaches for the conformation-selective detection of proteins in biological tissues .

• Collaborate with national and international experts in native protein MS to develop workflows enabling the detection of macromolecular conformational isomers in biological tissues.

• Collaborate with structural biologists on the interpretation of data and finding meaningful model systems for testing the novel workflows

• Work with bioinformatics experts within the Franklin and Member Institutions to extract macromolecular signals from MSI datasets

• Work with MS experts and structural biologists from the Member Institutions and broader UK user community to understand the broader context of the application

• Develop the scientific scope of the project, formulate relevant research questions, conduct individual research, analysing detailed and complex qualitative and/or quantitative data from a variety of sources, and generate original ideas by building on existing concepts

• Publish research articles in leading academic journals.

• Present findings at national and international meetings/conferences.

• Take a formal or informal role (as required) in the supervision of research students, including recruitment, mentorship and career development.

• Raise research funds through grant applications, and manage own area of a larger research budget

• Participate in and support the public engagement and widening access activities of the Franklin

• Any other duties that come up in the normal running of the facility and that can be reasonably requested of the post-holder.

Selection criteria

Essential

• A post-graduate qualification, or equivalent experience, in Chemistry, Physics, Engineering, Biomolecular Science, or related subjects.

• Experience in protein isolation and analysis

• Experience in protein mass spectrometry, with particular emphasis on native protein analysis

• A demonstrated aptitude for MS data pre-processing and data analysis

• Experience with developing and validating analytical methods

• Experience with devising research questions and to develop strategies to address them

• Ability to work both independently and as part of a team

• Strong organisational and communication skills.

• Ability to travel regularly for working at the industrial partner’s facilities

• Experience with project management and demonstrated ability to deliver agreed milestones in a timely manner, adapt to changing priorities

• Ability to discuss and coordinate experiments with a variety of colleagues from different disciplines

Desirable

• Expert knowledge of ion mobility spectrometry, HDX and top-down protein sequencing

• Experience in structural biology, cryo-EM, X-ray diffraction

• Experience in molecular imaging technologies

• Experience of molecular dynamics simulation of macromolecular ions

• Knowledge of protein NMR spectroscopy, in particular NOESY experiments

• Experience with general analytical and structure elucidation techniques such as chromatography, NMR or electrophoresis etc.

Closing date: 27th January 2020, 9:00am

Area: Scientific

Location: Harwell/Germany

Type of Post: Full Time

Salary: Competitive

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