Wim F. Vranken

The CCPN data model for NMR spectroscopy: Development of a software pipeline

To address data management and data exchange problems in the nuclear magnetic resonance (NMR) community, the Collaborative Computing Project for the NMR community (CCPN) created a “Data Model” that describes all the different types of information needed in an NMR structural study, from molecular structure and NMR parameters to coordinates. This paper describes the development of a set of software applications that use the Data Model and its associated libraries, thus validating the approach. These applications are freely available and provide a pipeline for high‐throughput analysis of NMR data. Three programs work directly with the Data Model: CcpNmr Analysis, an entirely new analysis and interactive display program, the CcpNmr FormatConverter, which allows transfer of data from programs commonly used in NMR to and from the Data Model, and the CLOUDS software for automated structure calculation and assignment (Carnegie Mellon University), which was rewritten to interact directly with the Data Model. The ARIA 2.0 software for structure calculation (Institut Pasteur) and the QUEEN program for validation of restraints (University of Nijmegen) were extended to provide conversion of their data to the Data Model. During these developments the Data Model has been thoroughly tested and used, demonstrating that applications can successfully exchange data via the Data Model. The software architecture developed by CCPN is now ready for new developments, such as integration with additional software applications and extensions of the Data Model into other areas of research. Proteins 2005.

RECOORD: A Recalculated Coordinate Database of 500 Proteins from the PDB Using Restraints from the BioMagResBank

State‐of‐the‐art methods based on CNS and CYANA were used to recalculate the nuclear magnetic resonance (NMR) solution structures of 500+ proteins for which coordinates and NMR restraints are available from the Protein Data Bank. Curated restraints were obtained from the BioMagResBank FRED database. Although the original NMR structures were determined by various methods, they all were recalculated by CNS and CYANA and refined subsequently by restrained molecular dynamics (CNS) in a hydrated environment. We present an extensive analysis of the results, in terms of various quality indicators generated by PROCHECK and WHAT_CHECK. On average, the quality indicators for packing and Ramachandran appearance moved one standard deviation closer to the mean of the reference database. The structural quality of the recalculated structures is discussed in relation to various parameters, including number of restraints per residue, NOE completeness and positional root mean square deviation (RMSD). Correlations between pairs of these quality indicators were generally low; for example, there is a weak correlation between the number of restraints per residue and the Ramachandran appearance according to WHAT_CHECK (r = 0.31). The set of recalculated coordinates constitutes a unified database of protein structures in which potential user‐ and software‐dependent biases have been kept as small as possible. The database can be used by the structural biology community for further development of calculation protocols, validation tools, structure‐based statistical approaches and modeling. The RECOORD database of recalculated structures is publicly available from http://www.ebi.ac.uk/msd/recoord. Proteins 2005.

PDBe: Protein Data Bank in Europe

The Protein Data Bank in Europe (PDBe; pdbe.org) is a partner in the Worldwide PDB organization (wwPDB; wwpdb.org) and as such actively involved in managing the single global archive of biomacromolecular structure data, the PDB. In addition, PDBe develops tools, services and resources to make structure-related data more accessible to the biomedical community. Here we describe recently developed, extended or improved services, including an animated structure-presentation widget (PDBportfolio), a widget to graphically display the coverage of any UniProt sequence in the PDB (UniPDB), chemistry- and taxonomy-based PDB-archive browsers (PDBeXplore), and a tool for interactive visualization of NMR structures, corresponding experimental data as well as validation and analysis results (Vivaldi).

E-MSD: an integrated data resource for bioinformatics

The Macromolecular Structure Database (MSD) group (http://www.ebi.ac.uk/msd/) continues to enhance the quality and consistency of macromolecular structure data in the Protein Data Bank (PDB) and to work towards the integration of various bioinformatics data resources. We have implemented a simple form-based interface that allows users to query the MSD directly. The MSD atlas pages show all of the information in the MSD for a particular PDB entry. The group has designed new search interfaces aimed at specific areas of interest, such as the environment of ligands and the secondary structures of proteins. We have also implemented a novel search interface that begins to integrate separate MSD search services in a single graphical tool. We have worked closely with collaborators to build a new visualization tool that can present both structure and sequence data in a unified interface, and this data viewer is now used throughout the MSD services for the visualization and presentation of search results. Examples showcasing the functionality and power of these tools are available from tutorial webpages (http://www. ebi.ac.uk/msd-srv/docs/roadshow_tutorial/).

E-MSD: the European Bioinformatics Institute Macromolecular Structure Database

The E-MSD macromolecular structure relational database (http://www.ebi.ac.uk/msd) is designed to be a single access point for protein and nucleic acid structures and related information. The database is derived from Protein Data Bank (PDB) entries. Relational database technologies are used in a comprehensive cleaning procedure to ensure data uniformity across the whole archive. The search database contains an extensive set of derived properties, goodness-of-fit indicators, and links to other EBI databases including InterPro, GO, and SWISS-PROT, together with links to SCOP, CATH, PFAM and PROSITE. A generic search interface is available, coupled with a fast secondary structure domain search tool.

DRESS: a database of refined solution NMR structures

Several studies have shown that biomolecular NMR structures are often of lower quality when compared to crystal structures, and consequently they are often excluded from structural analyses. We present a publicly available database of re‐refined NMR structures, exhibiting significantly improved quality. This database (available at http://www.cmbi.kun.nl/dress/) presents a uniformly refined and validated set of structural models that improves the value of these NMR structures as input for experimental and theoretical studies in many fields of research. Proteins 2004.

The CCPN project: an interim report on a data model for the NMR community.

A recent workshop discusses the progress toward integrating NMR data into a unifying data model.

EUROCarbDB: An open-access platform for glycoinformatics.

The EUROCarbDB project is a design study for a technical framework, which provides sophisticated, freely accessible, open-source informatics tools and databases to support glycobiology and glycomic research. EUROCarbDB is a relational database containing glycan structures, their biological context and, when available, primary and interpreted analytical data from high-performance liquid chromatography, mass spectrometry and nuclear magnetic resonance experiments. Database content can be accessed via a web-based user interface. The database is complemented by a suite of glycoinformatics tools, specifically designed to assist the elucidation and submission of glycan structure and experimental data when used in conjunction with contemporary carbohydrate research workflows. All software tools and source code are licensed under the terms of the Lesser General Public License, and publicly contributed structures and data are freely accessible. The public test version of the web interface to the EUROCarbDB can be found at http://www.ebi.ac.uk/eurocarb.

CASD-NMR: Critical Assessment of Automated Structure Determination by NMR

We report the completion of the first comparison of automated NMR protein structure calculation methods and announce its continuation in the form of an ongoing, community-wide experiment: CASD-NMR (Critical Assessment of Automated Structure Determination of Proteins by NMR). CASD-NMR is open for any laboratory to participate and/or to submit targets. n nNMR spectroscopy is the only technique for the determination of the solution structure of biological macromolecules. This typically requires both the assignment of resonances and a labor-intensive analysis of multidimensional NOESY spectra, where peaks are matched to assigned resonances. Software tools for the full automation of the NOESY assignment and the structure calculation steps have the potential to boost the efficiency, reproducibility and reliability of NMR structures. Within the e-NMR project (www.e-nmr.eu), which is funded by the European Commission (Project number 213010), we are developing an approach to assess whether such automated methods can indeed produce structures that closely match those manually refined using the same experimental data (the “reference structures”). The concept closely resembles that of other community-wide experiments, such as CASP, the Critical Assessment of Techniques for Protein Structure Prediction1, and CAPRI, the Critical Assessment of Prediction of Interactions2. At variance with both CASP and CAPRI, CASD-NMR is entirely based on experimental data, presenting special issues in assembling, organizing, and distributing these data among participants. n nWe provided seven research teams in the field with ten experimental data sets for various protein systems of known structure and two sets for protein structures not yet publicly available (“blind tests”), courtesy of the NorthEast Structural Genomics consortium (NESG). We then met in Florence, Italy on May 4–6, 2009 to analyze the structures generated (Fig. 1), by comparison to the reference structures and by using software tools for structure validation. This first experiment indicated that while most submissions had correct overall folds, on certain targets some programs failed to calculate accurate packing and length of secondary structure elements. The root mean square deviations (RMSDs) of the backbone coordinates from the manually-solved structures were typically in the 1–2 A range, but reached values as high as 9 A in some cases. n n n nFigure 1 n nPerformance of various automated structure calculation methods

A framework for scientific data modeling and automated software development

MOTIVATIONnThe lack of standards for storage and exchange of data is a serious hindrance for the large-scale data deposition, data mining and program interoperability that is becoming increasingly important in bioinformatics. The problem lies not only in defining and maintaining the standards, but also in convincing scientists and application programmers with a wide variety of backgrounds and interests to adhere to them.nnnRESULTSnWe present a UML-based programming framework for the modeling of data and the automated production of software to manipulate that data. Our approach allows one to make an abstract description of the structure of the data used in a particular scientific field and then use it to generate fully functional computer code for data access and input/output routines for data storage, together with accompanying documentation. This code can be generated simultaneously for different programming languages from a single model, together with, for example for format descriptions and I/O libraries XML and various relational databases. The framework is entirely general and could be applied in any subject area. We have used this approach to generate a data exchange standard for structural biology and analysis software for macromolecular NMR spectroscopy.nnnAVAILABILITYnThe framework is available under the GPL license, the data exchange standard with generated subroutine libraries under the LGPL license. Both may be found at http://www.ccpn.ac.uk; http://sourceforge.net/projects/ccpnnnnCONTACTnccpn@mole.bio.cam.ac.uk.