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Shedding light on biomolecular interactions

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Presentation SURF Research and Innovation Event 2013

February 28, The Hague University of Applied Sciences

Alexandre Bonvin is Professor of Computational Structural Biology at the Faculty of Science of Utrecht University.

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Shedding light on biomolecular interactions

  1. 1. Shedding light on biomolecularinteractions Prof. Alexandre M.J.J. Bonvin Bijvoet Center for Biomolecular Research Faculty of Science, Utrecht University the Netherlands a.m.j.j.bonvin@uu.nl
  2. 2. The molecular machinesand network of life
  3. 3. NMR and structural biology A SpronkNMR production (www.spronknmr.eu)
  4. 4. The NMR structure determination workflow
  5. 5. Exploiting GRID resources in structural biology… NMR data collection and processing SAXS data analysis # Number of dimensions 2 # INAME 1 1H # INAME 2 1H 12 2.137 2.387 1 T 0.000e+00 0.00e+00 - 0 2756 2760 0 14 2.387 4.140 1 T 0.000e+00 0.00e+00 - 0 2760 2752 0 32 1.849 4.432 1 T 0.000e+00 0.00e+00 - 0 2259 2257 0 36 1.849 3.143 1 T 0.000e+00 0.00e+00 - 0 2259 2587 0 Data assign ( resid 501 and name OO T) 39 1.760 4.432 1 ( resid 501 and name Z ) 1 T 40 1.760 1.849 ( resid 501 and name X ) 1 T 43 1.760 3.143 0.000e+00 0.000e+00 0.000e+00 0.00e+00 - 0.00e+00 - 0.00e+00 - 0 2260 2257 0 0 2260 2259 0 0 2260 2587 0 ( resid 501 and name Y ) 1 T 46 1.649 4.432 1.035e+05 0.00e+00 r 0 2583 2257 0 interpretation 47 1.649 1.849 1 T 0.000e+00 ( resid 2 and name CA ) -0.1400 0.15000 0.00e+00 - 0 2583 2259 0 assign ( resid 501 and name OO ) ( resid 501 and name Z ) ( resid 501 and name X ) ( resid 501 and name Y ) ( resid 3 and name CA ) -0.0100 0.15000 Computations Structure, dynamics & interactions  impact on research and health: - origin of disease - design of new experiments - drug design…
  6. 6. The Project A Worldwide e-Infrastructure for Contract n°: RI-261572 Project type: CP-CSA NMR and structural biology Duration: 36 months (Oct.2013) Project Coordinator: Total budget: 2’434’000 € Prof. Alexandre M.J.J. Bonvin, Utrecht University, NL EC Funding: 2’150’000 €The team: • Utrecht University, Bijvoet Center for Biomolecular Research, NL • Johann Wolfgang Goethe Universität Frankfurt a.M., Center for Biomolecular Magnetic Resonance DE • University of Florence, Magnetic Resonance Center, IT • Istituto Nazionale di Fisica Nucleare , Padova, IT • Raboud University, Nijmegen, NL • University of Cambridge UK • European Molecular Biology Laboratory, Hamburg, DE • Spronk NMR Consultancy, LT • Academia Sinica, TW
  7. 7. The Virtual Research Community
  8. 8. The WeNMR VRCeScience hub for NMR and structural biology
  9. 9. The WeNMR VRC Consultancy Third-party aggregation KnowledgeTutorials, Wiki Grid Services VRC Help Center Marketplace NEW! Portals SSO Blogs, news, events.. Exposure Facebook User
  10. 10. www.wenmr.eu
  11. 11. The WeNMR services portfolio
  12. 12. WeNMR platform (February 2013)• Largest VO in the life sciences• > 500 registered users (29% from outside the EU)• ~ 45 000 CPU cores• > 330 CPU years over the last 12 months• > 1.25 million jobs over the last 12 months• User-friendly access to Grid via web portals www.wenmr.eu
  13. 13. VO-registered user distribution Stats of Nov. 1st, 2012
  14. 14. VO registered user distribution Stats of Nov. 1st, 2012
  15. 15. CPU usage distributionNGI-NL 43%
  16. 16. CPU usage distributionNGI-NL 43%
  17. 17. CPU usage distribution 330 CPU years
  18. 18. A few examples: CS-Rosetta
  19. 19. CS-ROSETTACS-Rosetta score RMSD from native
  20. 20. CS-ROSETTA (not) web portal/Volumes/Home/Users/christophe/minirosetta_svn/bin/minirosetta.macosgccrelease -abinitio::increase_cycles1 -nstruct 10 -database /Volumes/Home/Users/christophe/minirosetta_database -frag3/Volumes/Home/Users/christophe/Dropbox/minirosetta_pcs_file/DATA/1NKU/FRAG_CS-ROSETTA/frag3.t000.rosetta.tab.gz -frag9/Volumes/Home/Users/christophe/Dropbox/minirosetta_pcs_file/DATA/1NKU/FRAG_CS-ROSETTA/frag9.t000.rosetta.tab.gz -abinitio::stage1_patch/Volumes/Home/Users/christophe/Dropbox/minirosetta_pcs_file/SCORE/score0_pcs1.wts_patch -abinitio::stage2_patch/Volumes/Home/Users/christophe/Dropbox/minirosetta_pcs_file/SCORE/score1_pcs1.wts_patch -abinitio::stage3a_patch/Volumes/Home/Users/christophe/Dropbox/minirosetta_pcs_file/SCORE/score2_pcs1.wts_patch -abinitio::stage3b_patch/Volumes/Home/Users/christophe/Dropbox/minirosetta_pcs_file/SCORE/score5_pcs1.wts_patch -abinitio::stage4_patch/Volumes/Home/Users/christophe/Dropbox/minirosetta_pcs_file/SCORE/score3_pcs1.wts_patch -native/Volumes/Home/Users/christophe/Dropbox/minirosetta_pcs_file/DATA/1NKU/idealized_1NKU.pdb -out:file:silent /Volumes/Home/Users/christophe/PCS_ROSETTA_RESULT/ABINITIO//1NKU_exact_N1_PCS1.silent-out:file:scorefile /Volumes/Home/Users/christophe/PCS_ROSETTA_RESULT/ABINITIO//1NKU_exact_N1_PCS1.sc-abinitio::rg_reweight 0.5 -abinitio::rsd_wt_helix 0.5 -abinitio::rsd_wt_loop 0.5 -abinitio::use_filters false -broker::setup/Volumes/Home/Users/christophe/Dropbox/minirosetta_pcs_file/RUN/././1NKU_exact/setup_pcs1.txt -run:protocol broker -overwrite -PCS:normalization_id 1 -in::file::native_exclude_res 1 2 3 4 5 6 7 8 9 172 173 174175 176 177 178 179 180 181 182 183 184 185 186 187 -mute core.scoring.methods.PCS.PcsEnergy -mute
  21. 21. CS-ROSETTAweb portal
  22. 22. CS-ROSETTA behindthe webserver
  23. 23. HADDOCK: Shedding light on biomolecular interactions
  24. 24. The network of life… Science 302, 1727 (2003)
  25. 25. Biomolecular interactions Protein-protein interaction + Cellular interactome Applications Our current knowledge
  26. 26. Information-driven HADDOCKing NMR titrations NMR crosssaturation mutagenesisCross-linking HADDOCK High Ambiguity Driven DOCKing x y j z iH/D exchange Other sources e.g. SAXS, cryoEM Bioinformatic predictions EFRGSFSHL EFKGAFQHV NMR anisotropy data EFKVSWNHM LFRLTWHHV IYANKWAHV EFEPSYPHI RDCs, para-restraints, diffusion anisotropy Dominguez, Boelens & Bonvin. JACS 125, 173 (2003).
  27. 27. What can we learn from 3D structures (models) of complexes? • Models provide structural insight into function and mechanism of action • Models can drive and guide experimental studies • Models can help understand and rationalize the effect of disease- related mutations • Models provide a starting point for drug design
  28. 28. Haddockweb portal
  29. 29. User friendly easy interface > 2850 registered users (>150 with grid access) > 40000 served runs since June 2008 ~ 12% on the GRID
  30. 30. What is happening behind the scene?
  31. 31. HADDOCK world maphttp://www.targetmap.com/viewer.aspx?reportId=16513
  32. 32. Shedding light on complex interactions
  33. 33. The biomolecular recognitiondance... Wu et al. Glycobiology 2007
  34. 34. The HADDOCK PDB structure gallery >100 entries – Jan. 2013 Image collage from http://www.pdb.org
  35. 35. Predicting interactomes by docking… a dream?
  36. 36. The dark side of the interactome... Open challenges
  37. 37. Released on YouTube, featuring WeNMR: Search with as keywords: EGI cone snail
  38. 38. AcknowledgmentsThe teamAlexandre M.J.J. Bonvin Ivano Bertini Rolf BoelensAndrea Giachetti Johan van der Zwan Sjoerd J. de VriesAntonio Rosato Lucio Ferella Stefano Dal PraAnurag Bagaria Marc van Dijk Torsten HerrmannChristophe Schmitz Marco Verlato Tsjerk A. WassenaarEric Frizziero Mikael Trellet Victor JaravineGijs van der Schot Mirco Mazzucato Wim F. VrankenHarald Schwalbe Nuno Loureiro-Ferreira Danny HsuHendrik R. A. Jonker Peter Güntert Simon LinThe partners Utrecht University, Bijvoet Center for Biomolecular Research, NL Johann Wolfgang Goethe Universität Frankfurt a.M., Center for Biomolecular Magnetic Resonance DE University of Florence, Magnetic Resonance Center, IT Istituto Nazionale di Fisica Nucleare , Padova, IT Raboud University, Nijmegen, NL University of Cambridge UK European Molecular Biology Laboratory, Hamburg, DE Spronk NMR Consultancy, LT Academia Sinica
  39. 39. Acknowledgements VICI NCF (BigGrid) BioNMR WeNMR DDSG
  40. 40. www.capri2013.nl

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