Shedding light on biomolecular interactions

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

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

Facebook

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