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World-wide E-infrastructure for structural biology

Periodic Reporting for period 2 - West-Life (World-wide E-infrastructure for structural biology)

Reporting period: 2017-05-01 to 2018-10-31

Structural biology is a discipline within the life sciences, one that investigates the molecular basis of life by discovering and interpreting the shapes of macromolecules. Structural biology has a strong tradition of data sharing, expressed by the founding of the Protein Data Bank (PDB) in 1971.

The physical infrastructure for structural biology includes synchrotrons, which are affordable only by a nation. Each synchrotron provides a number of beamlines for experiments, usually including several optimised for macromolecular X-ray crystallography, often some for other structural biology techniques including SAXS (Small-Angle X-Ray Scattering) and CD (Circular Dichroism), and usually some beamlines for material sciences and other non-biological applications.

A single instrument for NMR (Nuclear Magnetic Resonance) is usually affordable by a university or a company. However, multiple instrument must be used for NMR-based structural biology, because of the need for experiments at different magnetic fields. Thus, typically, investments of the order of 5-10 million euros are required.

Improvements in microscopes, direct electron detectors, and processing software have led to a rapid increase in the number of high resolution cryoEM structures - the “resolution revolution”. This has led in turn to significant investments in electron microscopes around Europe, including dedicated facilities such as NeCEN in Leiden and eBIC at Diamond. Experiments on these instruments produce terabyte datasets.

Getting benefit from these instruments depends on processing the results with computers. Moreover, structural biologists are choosing harder targets each year as they seek to understand the macromolecular machinery of life. Expertise in a single experimental method is not enough to solve these systems. Another difficulty is the burden of installing and learning to use a wide range of software.

West-Life has helped by cloud provisioning of software, and by integrating existing services into combined pipelines. West-Life has thus matched services from the emerging European Open Science Cloud to the emerging research methods in structural biology.
The project has enabled improvements to ten different web services for structure determination. West-Life has also participated in the development of the new services: DipCheck for validation protein backbone geometry, PRODIGY for the prediction of binding affinities for protein-protein complexes and protein-small ligand binding, SpotOn for the identification of hot-spot residues in protein complexes, 3DBionotes for annotating structures with biochemical and biomedical information, and Dipcheck for validating protein backbone geometry, and new algorithms were added to ARP/wARP to suport cryo-Electron Microscopy.

The project also built pipelines combining existing services. These are shown in the attached diagram. The West-Life Portal provides links to these services. Use of these services has increased by 25-40% iper year (D5.8). To do all this, we collaborated with other European projects.
West-Life has created new services for processing experimental data, and joined up existing services into pipelines. This supports structural biologists in their research, and in particular ensures that structural biology benefits from the European investment in e-Infrastructure.

This research has benefits for fundamental knowledge and for biomedical applications. Fruzsina Hobor at the University of Leeds was researching into a recently discovered mechanism for cell–cell communication that is important to the development and function of a broad range of tissues. Robert Dagil, University of Copenhagen, studied the causes of side-effects of the anti-biotic Gentamicin. Nelly Morellet, University of Paris, studied potential genetic therapies. Zorica Latinović, Jožef Stefan Institute (Ljubljana) studied a snake venom that has potential as the basis for anticoagulant drugs. All of these research projects used West-Life services.
"The West-Life ""interactome"""