General information

Organisation:  Utrecht University is the largest university in the Netherlands. Its Faculty of Science hosts the Bijvoet Center for Biomolecular Research, a joint research institute of Utrecht University and the Chemical Sciences Research Council (NWO-CW) whose research focuses on mechanisms of molecular recognition and interactions.

Description of the laboratory: The reaserch work of Partner 8 is carried out within the NMR Research group of the Chemistry Department, Faculty of Science. The research of the UU partner aims at obtaining fundamental insight on biological processes using the methods of high-resolution NMR spectroscopy. A major goal is to understand biomolecular recognition processes in terms of detailed 3D structures and dynamics.
The UU partner possesses expertise in fields such as molecular biology, protein expression, development of new NMR methodology and its application to biomolecular systems, and development and application of computational and molecular modelling approaches. In the past, relaxation matrix-based structure refinement methods and validation software have been developed (IRMA, DINOSAUR, AQUA). The group has developed the data-driven docking approach HADDOCK, which is now used by more than 400 research groups worldwide.
The NMR group has a long history in EC projects  (FP5 NMRQUAL and FIND, FP6  Extend-NMR, NDDP, NMRLife, EU-NMR). It also belongs to the large EU-funded Structural Genomics consortium SPINE-II complexe. The facilities of the UU partner comprises a modern molecular biology laboratory, state-of-the-art NMR equipment including a 900 MHz spectrometer with cryoprobe, and extensive computer facilities including a 48 processor opteron cluster dedicated to modeling and biomolecular docking.



Principal Investigators: Dr. Alexandre Bonvin is an associate professor within the faculty of Sciences. His expertise resides in computational structural biology and covers computational aspects of NMR, molecular dynamics simulations and modeling of biomolecular interactions. For the latter, he developed HADDOCK (High Ambiguity Driven protein-protein DOCKing) for the prediction of macromolecular complexes; this approach makes use of any available information on interactions from biochemical and biophysical experiments and/or bioinformatic predictions to drive the docking. Dr. Bonvin’s group has been particularly successful in the blind protein-protein docking competition CAPRI (Critical Assessment of PRediction of Interactions), scoring among the top groups worldwide. His research has resulted in over 85 publications.
Dr. Rolf Boelens, head of the NMR research group, is professor of biomolecular NMR spectroscopy and director of the high-resolution NMR facility at Utrecht, a part of the European large-scale NMR facilities. He has worked on EPR of metalloproteins, NMR spectroscopy of DNA binding and ribosomal proteins, methods development in biomolecular NMR spectroscopy, and computational methods. His current interests are biomolecular interactions with an emphasis on transcription and DNA repair. His research has resulted in over 250 publications.
Dr. Robert Kaptein, professor emeritus, is the former head of the NMR research group.

Recent relevant publications of the Utrecht partner:

• S.J. de Vries, A.D.J. van Dijk, M. Krzeminski, M. van Dijk, A. Thureau, V. Hsu, T. Wassenaar & A.M.J.J. Bonvin (2007). HADDOCK versus HADDOCK: New features and performance of HADDOCK2.0 on the CAPRI targets. Proteins: Struc. Funct. & Bioinformatic, advanced online publication.

• E. AB, D.J.R. Pugh, R. Kaptein, R. Boelens and A.M.J.J. Bonvin (2006).Direct Use of Unassigned Resonances in NMR Structure Calculations with Proxy Residues. J. Am. Chem. Soc., 128, 7566-7571 (2006).

• A.D.J. van Dijk and A.M.J.J. Bonvin (2006). Solvated docking: introducing water into the modelling of biomolecular complexes. Bioinformatics, 22 2340-2347.
• M. van Dijk, A.D.J. van Dijk, V. Hsu, R. Kaptein, R. Boelens & A.M.J.J (2006). Bonvin. Information-driven Protein-DNA Docking using HADDOCK: it is a matter of flexibility. Nucl. Acids Res. 34, 3317-3325.
• A.M.J.J. Bonvin (2006). Flexible protein-protein docking. Curr. Opin. Struct. Biol., 16, 194-200.

• A.J. Nederveen, J.F. Doreleijers, W. Vranken, Z. Miller, C.A.E.M. Spronk, S.B. Nabuurs, P. Guntert, M. Livny, J.L. Markley, M. Nilges, E.L. Ulrich, R. Kaptein and A.M.J.J. Bonvin (2005). RECOORD: a REcalculated COORdinates Database of 500+ proteins from the PDB using restraints from the BioMagResBank. Proteins: Struc. Funct. & Bioinformatics, 59, 662-672.

• A. D. J. van Dijk, R. Boelens & A. M. J. J. Bonvin (2005). Data-driven docking for the study of biomolecular complexes. FEBS Journal, 272, 293-312.
• C. Dominguez, R. Boelens & A.M.J.J. Bonvin (2003). HADDOCK: A protein-protein docking approach based on biochemical or biophysical information. J. Am. Chem. Soc. 125, 1731-1737.

Workpackages

Partner 8 is mainly involved in workpackage 2 with smaller contributions to workpackages 3 and 5.

Contributions of Partner 8 to WP2 "Development of new tools for spectral assignment and structure determination":

• Development of a protein-DNA docking approach accounting for flexibility on the DNA side (contribution to D4 improved structure calculation tools). This work has already let to an article in Nucleic Acid Research (van Dijk et al. 2006). This is incorporated into the latest HADDOCK release (HADDOCK2.0, May 22nd 2007).

• Development of a protocol to incorporate interfacial water molecules into the modeling of biomolecular complexes using HADDOCK (contribution to D4 improved structure calculation tools). An article describing this work has been published in Bioinformatics (van Dijk and Bonvin, 2006).
• Development of a procedure to incorporate unassigned resonances into the automated NOE assignment / structure calculation process (contribution of M2.1, D6, structure calculation tools that do not require a prior spectral assignment step.).  Modified structure calculations scripts and libraries are available from: http://www.nmr.chem.uu.nl/proxies . This work has led to a publication in JACS (AB et al. 2006).

Contributions of Partner 8 to WP5 "Testing, validation and documentation":

• We have provided complete NMR datasets including raw NMR data, assignments, peak and restraints files for three complexes (contribution to M5.1, D2, collection and analysis of existing NMR data sets):

  - An obligate homodimer (BASP, 2BXB)
  - An obligate heterodimer (ERCC1/XPF, 1Z00)
  - A protein-small ligand (non covalent co-factor) complex  (AppA,  2BUN)