WeNMR: Structural Biology on the Grid

0 T. Herrmann Centre de RMN trs Hauts Champs, Institut des Sciences Analytiques, Universit de Lyon , UMR-5280 CNRS, ENS Lyon, UCB Lyon 1, 5 rue de la Doua, 69100 Villeurbanne, France 1 G. W. Vuister Department of Biochemistry, School of Biological Sciences , Henry Wellcome Building, University of Leicester , Lancaster Road, Leicester LE1 9HN, UK 2 G. Vriend CMBI, Radboud University Nijmegen Medical Centre , Geert Grooteplein 26-28, Nijmegen, The Netherlands 3 J. F. Doreleijers Protein Biophysics/IMM, Radboud University Nijmegen , Geert Grooteplein 26-28, Nijmegen, The Netherlands 4 W. F. Vranken European Bioinformatics Institute , Hinxton, Cambridge , CB10 1SD, UK 5 Present Address: W. F. Vranken Department of Structural Biology , VIB, and Structural Biology Brussels, Vrije Universiteit Brussel , Pleinlaan 2, 1050 Brussels, Belgium 6 Present Address: N. Loureiro-Ferreira European Grid Infrastructure (EGI), 140 Science Park , 1098 XG Amsterdam, The Netherlands 7 Present Address: T. A. Wassenaar Biocomputing Group, Department of Biological Sciences, University of Calgary, 2500 University Drive NW , AB T2N 1N4 Calgary, Canada The WeNMR (http://www.wenmr.eu) project is a European Union funded international effort to streamline and automate analysis of Nuclear Magnetic Resonance (NMR) and Small Angle X-Ray scattering (SAXS) imaging data for atomic and near-atomic resolution - molecular structures. Conventional calculation of structure requires the use of various software packages, considerable user expertise and ample computational resources. To facilitate the use of NMR spectroscopy and SAXS in life sciences the WeNMR consortium has established standard computational workflows and services through easy-to-use web interfaces, while still retaining sufficient flexibility to handle more specific requests. Thus far, a number of programs often used in structural biology have been made available through application portals. The implementation of these services, in particular the distribution of calculations to a Grid computing infrastructure, involves a novel mechanism for submission and handling of jobs that is independent of the type of job being run. With over 450 registered users (September 2012), WeNMR is currently the largest Virtual Organization (VO) in life sciences. With its large and worldwide user community, WeNMR has become the first Virtual Research Community officially recognized by the European Grid Infrastructure (EGI). 1 Introduction 1.1 NMR Spectroscopy NMR Spectroscopy is one of two main techniques that allow determining three dimensional (3D) structures of biomacromolecules, such as proteins, RNA, DNA, and their complexes, at atomic resolution. Knowledge of their 3D structures is vital for understanding functions and mechanisms of action of macromolecules, and for elucidating and predicting the effect of mutations. 3D structures are also important as guides for the design of new experimental studies and as starting points for rational drug design. An advantage of NMR over X-ray crystallography is that it also allows investigation of time-dependent chemical and conformational phenomena, including reaction and folding kinetics and intramolecular dynamics. For these reasons, NMR plays an important role within the life sciences. The principles underlying NMR are modulation of the natural magnetic moment of atomic nuclei, and measurements of how the system relaxes back to the initial state [1, 2]. The signal thus obtained is a fading wave consisting of many individual frequency contributions: the Free Induction Decay, FID. Typically, up to 27000 different frequencies can be resolved at the highest magnetic fields that are nowadays available. To investigate the frequency contributions and their decays, such measurements have to be repeated many times, due to the low signal-to-noise ratio. To obtain structural information from NMR data, many more, but also more complex measurements have to be run, yielding substantial amounts of data that need processing. Processing data from NMR to obtain a 3D structure typically involves the following steps, summarized graphically in Fig. 1. First the raw data have to be processed, more specifically Fourier-transformed, to obtain spectra revealing the different frequency contributions and their relations. These frequencies are the resonances of the atoms measured, but to infer structural information from them, these resonances subsequently have to be assigned to individual contributors (atoms/residues). If the assignment is sufficiently complete, structural restraints can be determined Fig. 1 NMR data processing from signal to 3D structure. After acquisition of the primary NMR data, these are Fourier transformed to obtain spectra in which the individual frequency contributions or resonances of spin systems, and their relations, are revealed. The resonances subsequently have to be assigned to individual atoms. If sufficient resonances have been assigned, restraints can be inferred from the data, pertaining to distances between atoms, dihedral angles, domain orientations, etc. When an adequate number of restraints is available, these can be used to calculate a set of three-dimensional structures optimally satisfying these restraints. The resulting structures represent the structure of the protein in solution, which is validated against the available experimental data. Although the process is here depicted linearly, intermediate stages may involve iterative cycles of refinement from the spectra, including inter-atomic distance restraints, dihedral angle restraints, and orientation restraints. These structural restraints are then used to calculate a number of structures using a variety of molecular modeling approaches, after which structure validation checks are performed to assert the quality of the results. For each of the steps involved, specialized computer programs are available, each with its own characteristics and often with its own data format. Processing of NMR data has thus become a task for specialists, who can understand the data and their formats, as well as the programs, with installation requirements and usage details. Furthermore, NMR data processing requires considerable data storage and computational resources. These factors together currently represent a barrier for groups in life sciences to employ the full power of NMR. Against this background, the eNMR project was run as a European initiative funded under the Framework 7 e-Infrastructure programme to considerably facilitate this process [3]. It is now carried on by the WeNMR (a Worldwide e-Infrastructure for NMR and structural biology) project since November 2010. The project aims at allowing groups lacking the resources to add NMR to their toolbox, as well as allowing dedicated NMR groups to improve their standard from basic practice towards cutting-edge research. 1.2 Small Angle X-Ray Scattering Small Angle X-Ray Scattering (SAXS) is a widely used (...truncated)