Objective
No-one could have foreseen that Julian Schwinger's calculations on the energy changes encountered by an electron moving on a circular path could result in construction of tools that have had a major impact on biological sciences and the discovery of new pharmaceuticals. Over the past twenty years synchrotron radiation has been successfully applied to a wealth of fundamental problems in life sciences, yielding dramatic improvements in the understanding of biological and chemical phenomena. Recent successes have also witnessed atomic resolution imaging using X-ray holography. A closely related area of new developments is electron diffraction, offering direct ways for atomic resolution structure determinations on crystals many million times smaller than those used in routine X-ray studies.
Given the tremendous importance of diffraction techniques within structural biology, it is highly pertinent to ask: Where does crystallography go from here? The objective of this proposal is to initiate in Europe theoretical and experimental studies to explore untried frontiers at the physical limits of macromolecular imaging. Within this proposal, we plan to utilise current technology but we also anticipate the imminent emergence of new electron and X-ray sources capable of producing intense and coherent radiation pulses of femtosecond-attosecond durations. Our preliminary calculations based on optimal boundary conditions indicate such electron or photon pulses may allow the direct imaging of Fourier transforms of single macromolecules, viruses or larger structures without the need to amplify scattered radiation through Bragg reflections. This area is virtually unexplored. As the potential benefits from studies in these field are substantial, a comprehensive and rigorous investigation of these ideas is necessary and timely.
The planned work combines long-term objectives with immediate deliverables. Paramount within the programme is the need to determine theoretically the smallest sample size from which it may be physically possible to obtain useful structural information. This may be a single molecule (could we get rid of the crystal in crystallography?), a closed periodic cluster of molecules, or an open periodic structure (nanocrystals, microcrystals). In WORK PACKAGE 1, we will study theoretically the dynamics of Xray and electron scattering from biomolecules and their multimers in ultrashort exposure times at high radiation intensities. We will asses time-dependent components in radiation damage and their effect on image quality as a function of dose, pulse length, sample size, sample dynamics, and signal to noise ratio (Budapest, Karlsruhe, Uppsala, Stockholm).
The main experimental aim of the proposal is to develop methods for the preparation, characterisation and handling of nanocrystals, nanoclusters and single molecules. This has immediate relevance to electron microscopy and crystallography. In WORK PACKAGE 2 procedures will be developed for assembling proteins of choice into regular nanoclusters or nanocrystals (Uppsala). Methods will be developed for the specific attachment of target proteins to the surface of icosahedral virus capsids. WORK PACKAGE 3: With ultrasmall samples, standard procedures for sample selection, characterisation and handling will no longer be appropriate. We will develop novel electrospray techniques (Oxford) to select and collect single particles and nanoclusters of molecules on electron microscopy grids inside the mass spectrometer. WORK PACKAGE 4: The samples will then be used for structural studies by electron cryomicroscopy and electron diffraction (Stockholm, London). The methods will be applied to studies on both soluble and membrane proteins.
Keywords: nanocrystals, nanoclusters, mass spectrometry, single molecule imaging, ultrafast diffraction methods, X-ray diffraction, electron diffraction, holographic data processing, electron cryomicroscopy, membrane protein structure
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- natural sciences earth and related environmental sciences geology mineralogy crystallography
- natural sciences biological sciences biochemistry biomolecules proteins
- natural sciences physical sciences optics microscopy electron microscopy
- natural sciences computer and information sciences data science data processing
- natural sciences biological sciences molecular biology structural biology
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Multi-annual funding programmes that define the EU’s priorities for research and innovation.
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Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
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Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
Coordinator
751 23 UPPSALA
Sweden
The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.