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Extending NMR for functional and structural genomics.

Final Report Summary - EXTEND-NMR (Extending NMR for functional and structural genomics)

The main objective of this project was to develop novel computational tools that extend the scope of nuclear magnetic resonance (NMR) spectroscopy and make possible functional and structural studies of larger proteins and biomolecular complexes. To achieve this, our main aim was to tightly integrate existing state-of-the-art NMR software packages into a computational pipeline. The EXTEND-NMR project also wanted to develop and integrate novel computational tools which address two important bottlenecks in NMR. In particular we wanted to develop new techniques that:
1) allow the identification and quantification of NMR signals; and
2) allow the rapid assignment of NMR spectra and structure calculation.
Secondly, we are interested in the development of tools that allow the calculation of structures of more complex systems – larger proteins, complexes, and membrane proteins in the solid state.

These objectives were facilitated by the development and implementation of a series of computational algorithms as well as statistical- and expert system-based analysis tools. The software and algorithms were implemented within a common software framework developed by the Collaborative Computing Project for the NMR community (CCPN), so that they could be flexibly employed in the development of the different tools. The tools were combined through the development of a graphical user interface to enable users to make full use of the software. We now intend to test the pipeline we have developed on a new protein target as a proof of concept.

It is essential that the software pipeline and its components remain functional after the EXTEND-NMR project is finished, and that the results obtained in its context are used for further software development, and to further aid the NMR community.

Subsequently, the amount of data stored in CCPN projects was further extended, both for public archived data and for specific lab based data. The existing archived data projects containing constraint and coordinate data are continuously updated as part of a collaboration with the BioMagResBank (BMRB), and a new set of projects was created where chemical shift information is linked to coordinate data. The constraint information was used for software testing within the EXTEND-NMR project, and now forms the basis of a new structure recalculation effort. The chemical shift information was extensively analysed, and a new method was developed to validate and correct the individual chemical shift values in relation to the coordinates. The large cleaned up data sets obtained this way have already led to much improved software for the prediction of chemical shift values for unfolded proteins, and paved the way for new implementations and collaborations in this field. The specific lab based data was used as part of software testing in the ENMR project, and is now available for testing of the EXTEND-NMR pipeline.

This extensive data pool is now available to test the EXTEND-NMR pipeline. To minimise the work required for testing the components, an automated test setup was developed, which will help to identify problems with future versions of the software, and make sure that connections between software components are regularly checked. The setup does not yet encompass all the EXTEND-NMR software, but it is working for the FormatConverter, ARIA, HadDock and CING, and will be further extended. The individual partners have also performed extensive testing on their own software.

The connection to the community is maintained by providing easily accessible online documentation, both for the project itself and for the individual software components. Furthermore, a conference including an extensive demonstration of the software was held in Berlin in autumn 2008, and the current state of the EXTEND-NMR pipeline was demonstrated at the EUROMAR conference in Goteborg in July 2009. The entire EXTEND-NMR pipeline will be released as a single installation; work on the release is in the final phase of testing and problem solving. The code will be released as both source code and pre-compiled versions from the public CCPforge server and in the form of release DVDs.

The results of the EXTEND-NMR project will mainly be distributed to the international research community as open source programs, which will be free for non-profit organisations. NMR software generally does not lend itself to commercial exploitation, given the limited size of the target groups, and the existence of competing freely available programs. The programs produced by EXTEND-NMR can all be accessed through the EXTEND-NMR web site: http://www.extend-nmr.eu. They are further disseminated through publications, scientific conference presentations, courses and workshops by the EXTEND-NMR partners.

The exception is the interface between the new software and the NMR processing program TOPSPIN. TOPSPIN has a large market share among NMR spectrometer users and reaches beyond university research groups. By adding extra capabilities to TOPSPIN the new interfaces make it more attractive to Bruker customers, and they also make the EXTEND-NMR software available to a larger audience. The EXTEND-NMR software is in principle available for integration with other commercial NMR packages, but the integration code has been developed specifically for TOPSPIN and can therefore confer a commercial advantage to Bruker.

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