shedding light on biomolecular interactions
DESCRIPTION
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.TRANSCRIPT
Shedding light on biomolecular interactions
Prof. Alexandre M.J.J. Bonvin
Bijvoet Center for Biomolecular Research
Faculty of Science, Utrecht University
the Netherlands
The molecular machines and network of life
NMR and structural biology
A SpronkNMR production (www.spronknmr.eu)
The NMR structure determination workflow
# Number of dimensions 2# INAME 1 1H# INAME 2 1H12 2.137 2.387 1 T 0.000e+00 0.00e+00 - 0 2756 2760 014 2.387 4.140 1 T 0.000e+00 0.00e+00 - 0 2760 2752 032 1.849 4.432 1 T 0.000e+00 0.00e+00 - 0 2259 2257 036 1.849 3.143 1 T 0.000e+00 0.00e+00 - 0 2259 2587 039 1.760 4.432 1 T 0.000e+00 0.00e+00 - 0 2260 2257 040 1.760 1.849 1 T 0.000e+00 0.00e+00 - 0 2260 2259 043 1.760 3.143 1 T 0.000e+00 0.00e+00 - 0 2260 2587 046 1.649 4.432 1 T 1.035e+05 0.00e+00 r 0 2583 2257 047 1.649 1.849 1 T 0.000e+00 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 2 and name CA ) -0.1400 0.15000
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
Datainterpretation
Structure, dynamics & interactions impact on research and health:
- origin of disease- design of new experiments- drug design…
Exploiting GRID resources in structural biology…
Computations
NMR data collection and processing SAXS data analysis
Project Coordinator:Prof. Alexandre M.J.J. Bonvin, Utrecht University, NL
Contract n°: RI-261572Project type: CP-CSADuration: 36 months (Oct.2013)Total budget: 2’434’000 €EC Funding: 2’150’000 €
A Worldwide e-Infrastructure for NMR and structural biology
• 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
The team:
The Project
The Virtual Research Community
eScience hub for NMR and structural biology
The WeNMR VRC
The WeNMR VRC
Knowledge
Help Center
Tutorials, Wiki
Consultancy
Services
Portals
VRC
Third-party aggregation
Grid
Exposure
Marketplace
Blogs, news,events..
User
NEW!
SSO
www.wenmr.eu
The WeNMR services portfolio
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
VO-registered user distribution
Stats of Nov. 1st, 2012
VO registered user distribution
Stats of Nov. 1st, 2012
CPU usage distribution
NGI-NL 43%
CPU usage distribution
NGI-NL 43%
CPU usage distribution
330 CPU years
A few examples: CS-Rosetta
CS-ROSETTA
RMSD from native
CS-
Ro
sett
a sc
ore
/Volumes/Home/Users/christophe/minirosetta_svn/bin/minirosetta.macosgccrelease -abinitio::increase_cycles 1 -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 9 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 -mute core.scoring.methods.PCS.PcsEnergy -mute core.optimization.LineMinimizer
CS-ROSETTA (not) web portal
CS-ROSETTAweb portal
CS-ROSETTA behind the webserver
HADDOCK: Shedding light on biomolecular interactions
Science 302, 1727 (2003)
The network of life…
Biomolecular interactions
+
Protein-protein interaction
Cellular interactome
Applications
Our current knowledge
i
xyzj
HADDOCK High Ambiguity Driven DOCKing
mutagenesis
NMR titrations
Cross-linking
H/D exchange
EFRGSFSHL
EFKGAFQHV
EFKVSWNHM
LFRLTWHHV
IYANKWAHV
EFEPSYPHI
Bioinformatic predictions
NMR anisotropy data
RDCs, para-restraints, diffusion anisotropy
NMR crosssaturation
Other sourcese.g. SAXS, cryoEM
Dominguez, Boelens & Bonvin. JACS 125, 173 (2003).
Information-driven HADDOCKing
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
Haddockweb portal
User friendly easy interface
> 2850 registered users
(>150 with grid access)
> 40000 served runs since June 2008
~ 12% on the GRID
What is happening behind the scene?
HADDOCK world map
http://www.targetmap.com/viewer.aspx?reportId=16513
Shedding light on complex interactions
Wu et al. Glycobiology 2007
The biomolecular recognition dance...
The HADDOCK PDB structure gallery
>100 entries – Jan. 2013
Image collage from http://www.pdb.org
Predicting interactomes by docking…
a dream?
The dark side of the interactome...
Open challenges
Released on YouTube, featuring WeNMR:
Search with as keywords:EGI cone snail
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
The partners
The team
Alexandre M.J.J. BonvinAndrea GiachettiAntonio RosatoAnurag BagariaChristophe SchmitzEric FrizzieroGijs van der SchotHarald SchwalbeHendrik R. A. Jonker
Ivano BertiniJohan van der ZwanLucio FerellaMarc van DijkMarco VerlatoMikael TrelletMirco MazzucatoNuno Loureiro-FerreiraPeter Güntert
Rolf BoelensSjoerd J. de VriesStefano Dal PraTorsten HerrmannTsjerk A. WassenaarVictor JaravineWim F. VrankenDanny HsuSimon Lin
Acknowledgments
Acknowledgements
DDSG
VICINCF (BigGrid)
BioNMRWeNMR
www.capri2013.nl