DAS for Molecular Interactions Hagen Blankenburg

DAS for Molecular Interactions10/03/ 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“, … Level of detail 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 Biochemical pathways

Hagen BlankenburgDAS for Molecular Interactions10/03/ Problem I: Data abundance and distribution Scientific impact Too little bioinformatics Too many databases Too diverse interfaces (Credit: Tim Hubbard)

Hagen BlankenburgDAS for Molecular Interactions10/03/ 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-throughput experiments 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 BlankenburgDAS for Molecular Interactions10/03/ Problem II: Data quality MINT STRING IntAct APID 3DID PIPs

Hagen BlankenburgDAS for Molecular Interactions10/03/ Solution: Distributed System Interaction data serversInteraction confidence scoring servers Problem I: Data abundance and distributionProblem II: Data quality

Hagen BlankenburgDAS for Molecular Interactions10/03/ DAS for Molecular Interactions (DASMI) - Servers UniProtKB: P51587, BRCA2_HUMAN Entrez Gene: 675 GeneInfo: , , , , , , , , , RefSeq: NP_ , NM_ IPI: IPI Ensembl: ENSG Servers have coordinate / identifier systems

Hagen BlankenburgDAS for Molecular Interactions10/03/ DAS for Molecular Interactions (DASMI) - Registry

Hagen BlankenburgDAS for Molecular Interactions10/03/ DAS registry – Domain interactions Protein interactions All DAS servers with interaction capability Maintained at Sanger Institute 533 servers 52 institutions 16 countries

Hagen BlankenburgDAS for Molecular Interactions10/03/ DAS for Molecular Interactions (DASMI) - Data exchange DAS 1.53E data exchange specification &detail=property:bpscore <DASINT xmlns=" xmlns:xsi=" xsi:schemaLocation=" <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"/> DAS Request DASINT XML Response

Hagen BlankenburgDAS for Molecular Interactions10/03/ DAS for Molecular Interactions (DASMI) - Clients Clients merge interactors / interactions

Hagen BlankenburgDAS for Molecular Interactions10/03/ iPfam graphical domain interaction browser Interaction reported in both datasets Selected domain interaction servers

Hagen BlankenburgDAS for Molecular Interactions10/03/ DASMI Cytoscape Client Interactions reported by multiple datasets

Hagen BlankenburgDAS for Molecular Interactions10/03/ DASMI Cytoscape Client

Hagen BlankenburgDAS for Molecular Interactions10/03/ Predictions Literature curation / experiments Interaction reported by multiple datasets

Hagen BlankenburgDAS for Molecular Interactions10/03/ All confidence scoring methods that returned results for the current interactions

Hagen BlankenburgDAS for Molecular Interactions10/03/ Original confidence score provided by the authors

Hagen BlankenburgDAS for Molecular Interactions10/03/ Protein interactions supported by underlying domain interactions

Hagen BlankenburgDAS for Molecular Interactions10/03/ Details on domain interactions

Hagen BlankenburgDAS for Molecular Interactions10/03/ Functional similarity based on GO annotation of interactors

Hagen BlankenburgDAS for Molecular Interactions10/03/ 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 BlankenburgDAS for Molecular Interactions10/03/ 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