DAS for Molecular Interactions Hagen Blankenburg.

DAS for Molecular Interactions

Hagen Blankenburg

Hagen Blankenburg DAS for Molecular Interactions 210/03/2009

Importance of molecular interactions

Fundamental for

understanding of cellular

processes

Prediction of protein function

Importance in certain diseases

Essentiality of hub proteins?

The next big thing?!

„Interactomics“, „network

medicine“, …

Lev

el o

f d

etai

l

Gene-gene associations

Functional associations

Gene-gene coexpression

Literature relationships

Physical interactions

Binary PPI

Protein complexes

Physical interactions with structures

Binary PPI

Protein complexes

Protein-ligand interactions

Domain-domain interactions

Domain-domain interactions

Biochemical pathways

Hagen Blankenburg DAS for Molecular Interactions 310/03/2009

Problem I: Data abundance and distribution

Sci

enti

fic

im

pac

t

Too little bioinformatics Too many databases

Too diverse interfaces

(Credit: Tim Hubbard)

Hagen Blankenburg DAS for Molecular Interactions 410/03/2009

Problem II: Data quality

Replicate experiments Network topology Functional similarity Domain interactions Evolutionary conservation Co-localization Positive and negative

standard reference sets …

Replicate experiments Network topology Functional similarity Domain interactions Evolutionary conservation Co-localization Positive and negative

standard reference sets …

High quality

Low quality

High-throughputexperiments

Small-scale experiments

Computational predictions

Confidence measures:False

positives

Experimental biases

„Small-scale experiments are

more reliable than high-throughout

screens.“

„The results of Y2H screens are not trustworthy.“

Curation errors

False negatives

„Y2H screens are the most reliable

detection method.“

Prediction errors

„Computational predications are

inferior.“

Hagen Blankenburg DAS for Molecular Interactions 510/03/2009

Problem II: Data quality

MIN

T

ST

RIN

G

IntA

ct

AP

ID 3DID

PIP

s

Hagen Blankenburg DAS for Molecular Interactions 610/03/2009

Solution: Distributed System

Interaction data servers Interaction confidence scoring servers

Problem I: Data abundance and distribution Problem II: Data quality

Hagen Blankenburg DAS for Molecular Interactions 710/03/2009

DAS for Molecular Interactions (DASMI) - Servers

UniProtKB: P51587, BRCA2_HUMAN Entrez Gene: 675 GeneInfo: 119395734, 28400649, 1177438, 14424438, 2315186, 27065822, 37675289, 1161384, 16116616, RefSeq: NP_000050.2, NM_000059IPI: IPI00412408Ensembl: ENSG00000139618

Servers have coordinate / identifier systems

Hagen Blankenburg DAS for Molecular Interactions 810/03/2009

DAS for Molecular Interactions (DASMI) - Registry

Hagen Blankenburg DAS for Molecular Interactions 910/03/2009

DAS registry – http://www.dasregistry.org

Domain interactions

Protein interactions

All DAS servers with interaction capability

Maintained at

Sanger Institute

533 servers

52 institutions

16 countries

Hagen Blankenburg DAS for Molecular Interactions 1010/03/2009

DAS for Molecular Interactions (DASMI) - Data exchange

DAS 1.53E data exchange specification

http://www.dasmi.de/das/funsimmat/interaction?interactor=P09497&interactor=O60828 &detail=property:bpscore

<?xml version="1.0" encoding="UTF-8"?><DASINT xmlns="http://www.dasmi.de/" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" xsi:schemaLocation="http://www.dasmi.de/ http://www.dasmi.de/dasint.xsd"> <INTERACTOR intId="1" shortLabel="CLCB_HUMAN" dbSource="uniprotkb"dbSourceCvId="MI:0486" dbVersion="12.1" dbAccessionId="P09497" dbCoordSys="UniProt,Protein Sequence"/> <INTERACTOR intId="2" shortLabel="PQBP1_HUMAN" dbSource="uniprotkb" dbSourceCvId="MI:0486" dbVersion="12.1" dbAccessionId="O60828" dbCoordSys="UniProt,Protein Sequence"/> <INTERACTION name="P09497-O60828" dbSource="" dbAccessionId=""> <DETAIL property="bpscore" value="0.154429056459711"/> <PARTICIPANT intId="1"/> <PARTICIPANT intId="2"/> </INTERACTION></DASINT>

DAS Request

DASINT XML Response

Hagen Blankenburg DAS for Molecular Interactions 1110/03/2009

DAS for Molecular Interactions (DASMI) - Clients

Clients merge interactors / interactions

Hagen Blankenburg DAS for Molecular Interactions 1210/03/2009

iPfam graphical domain interaction browser

Interaction reported in both datasets

Selected domain interaction servers

Hagen Blankenburg DAS for Molecular Interactions 1310/03/2009

DASMI Cytoscape Client

Interactions reported by multiple datasets

Hagen Blankenburg DAS for Molecular Interactions 1410/03/2009

DASMI Cytoscape Client

Hagen Blankenburg DAS for Molecular Interactions 1510/03/2009

Predictions

Literature curation / experiments

Interaction reported by multiple datasets

http://www.dasmi.de/web

Hagen Blankenburg DAS for Molecular Interactions 1610/03/2009

All confidence scoring methods that returned results for the current interactions

http://www.dasmi.de/web

Hagen Blankenburg DAS for Molecular Interactions 1710/03/2009

Original confidence score provided by the authors

http://www.dasmi.de/web

Hagen Blankenburg DAS for Molecular Interactions 1810/03/2009

Protein interactions supported by underlying domain interactions

http://www.dasmi.de/web

Hagen Blankenburg DAS for Molecular Interactions 1910/03/2009

Details on domain interactions

http://www.dasmi.de/web

Hagen Blankenburg DAS for Molecular Interactions 2010/03/2009

Functional similarity based on GO annotation of interactors

http://www.dasmi.de/web

Hagen Blankenburg DAS for Molecular Interactions 2110/03/2009

Conclusions

Usage of DASMI servers and clients surprisingly good, but more

external DASMI servers are desirable

DAS client and server libraries (Dazzle, ProServer, (MyDAS),

Dasobert, Bio-DAS-lite) support DASMI

Considerable overlap with HUPO-PSI initiatives for distributed

interaction data retrieval (PSICQUIC) and confidence scoring

(PSISCORE)

Develop methods for combining different interaction confidence

scoring schemas in DASMI clients

& Outlook

Hagen Blankenburg DAS for Molecular Interactions 2210/03/2009

Acknowledgements

Joachim Büch

Fidel Ramírez

Dorothea Emig

Sven-Eric Schelhorn

Andreas Schlicker

Thomas Lengauer

Mario Albrecht

Robert Finn

Andreas Prlić

Jonathan Warren

Andrew Jenkinson

Henning Hermjakob