Protein-protein interaction networks

Protein‐ProteinInterac-onNetworksPredic-on,Visualiza-onandAnalysis

VijayarajNagarajanPhDComputa4onalMolecularBiologySpecialist

Bioinforma4csandComputa4onalBiosciencesBranch

Na4onalIns4tuteofAllergyandInfec4ousDiseasesOfficeofCyberInfrastructureandComputa4onalBiology

Outline•  Introduc4ontoInterac4onNetworks

•  Basiccomponentsofaninterac4onnetwork

•  Typesofinterac4onnetworks•  Predic4ngProtein‐ProteinInterac4onNetworks

•  Methods»  Logicandconcept

•  AvailableInterac4ondata•  Integratedprotein‐proteininterac4ondatabases•  Searchingforinterac4ondata

•  NetworkVisualiza4onandAnalysistools•  Popularvisualiza4ontools•  Networkanalysis

•  Demonstra4on•  Predic4onofinterac4on(PPI…?)networkfrommicroarray(ARACNE)

•  Visualiza4onandanalysisofthepredictednetwork(Cytoscape)

•  Nodes–  DNA/RNA/Protein/Metabolite

•  EdgesDirected

–  Dis4nc4onbetweensourceandtarget»  Ac4va4on(direct/indirect)»  Repression(direct/indirect)

Undirected

–  Nodis4nc4onbetweensourceandtarget»  Co‐expression(indirect)»  Binding(direct)

Interac-onNetworks–BasicComponents

Interac-onNetworks‐BasicFeatures•  Degree

•  Numberofconnec4onsthatanodehas

•  Distance•  Numberofconnec4onsbetweentwonodes,inashortestpath

•  Path•  Asequenceofconnec4ons•  Isthereapath(reachability)•  MeanShortestPathdistance(closeness)•  Inhowmanyshortestpaths(betweenness)

•  Sizeofanetwork(Numberofnodes)•  Densityofanetwork(Propor4onoftheconnec4ons)

•  Mo4fs/Cliques/Clusters/Sub‐networks

Chains

Parallels

Multi-input Single input

Interac-onNetworks‐BasicFeatures

TypesofInterac-onNetworks•  DNA‐Protein

»  Transcrip4onalregulatorynetworks»  Methyla4onnetworks

•  RNA‐RNA»  miRNAregulatorynetworks

•  RNA‐Protein»  Splicingregulatorynetworks

•  Protein‐Protein»  Co‐expressionnetworks»  Co‐localiza4onnetworks»  Co‐evolu4onnetworks»  Structurenetworks»  Pathwaynetworks»  Proteaseregulatorynetworks»  Signaltransduc4onnetworks»  GeneOntologynetworks

Singlegene

–  Regulators/Co‐regulators–  Upstream/Downstreamelementsinthenetwork

–  Globalconnec4vity/interconnec4vity–  Func4onalfeatures–  Differen4allyexpressedsubnetworks–  Onegene–onedisease:bunchofgenes–pathways–  Nextgensequencingdata

List of genes

WhyBuild/AnalyzeInterac-onNetworks?

HowtoBuildInterac-onNetworks?•  Search/Retrievefromknowledgebases•  Predictfromgenomesequences

•  Predictfrom“omics”data

•  Predictfromliterature•  Integrateandanalyze

Protein Engineering, Vol. 14, No. 9, 609-614, September 2001

Predic-onfromgenomesequences•  Geneneighbor(genecluster,geneorder)•  Genefusion(Rose\astone)•  Phylogene4cprofiling•  Co‐evolu4on•  Mirrortree

Predic-onfrom“omics”data•  Co‐expression(Correla4on,MutualInforma4on)

•  Integrated(Classifica4on)•  Literaturemining(NaturalLanguageProcessing)

AvailableInterac-onData•  MINT

•  MolecularInterac4onDatabase

•  BIND•  BiomolecularInterac4onNetworkDatabase

•  DIP•  DatabaseofInterac4ngProteins

•  IntAct•  InterAc4onDatabaseatEBI

IntegratedDataSources

•  PathwayCommons•  BioGRID

•  MiMI(MichiganMolecularInterac4ons)

•  STRING(SearchToolforRetrievalofInterac4ngGenes/Proteins)•  Genes2Network

•  VisANT(Integra4veVisualAnalysisTool)

•  BIOBASE•  IPA(IngenuityPathwayAnalysis)

•  MetaCore

Open Source

Proprietary

IP3Rs•  Inositoltriphosphatereceptor

•  ip3r1•  ip3r2•  ip3r3

»  Calciumionchannels

»  ER•  s4m1(stromalinterac4onmolecule1)

»  PM»  Calciumsensorprotein

•  orai1(calciumreleaseac4vatedcalciummodulator)»  PM

»  Accessoryproteindownstreamofs4m1

SearchingforInterac-onData

STRING

•  Cytoscape•  VisANT(Integra4veVisualAnalysisTool)•  Osprey•  BioLayout

PopularVisualiza-onTools

VisANT

AnalysisTools•  Phunkee(PairingsubgraphsUsingNetworkEnvironmentEquivalence–finds

similarsubnets)

•  mfinder(mo4fdetec4on)

•  MAVisto(Mo4fAnalysisandVisualiza4ontool–explora4onofmo4fs)

•  GraphMatch(Searchforsimilarsub‐nets)

•  NeAT(NetworkAnalysisTools–mo4ffinding,nodesta4s4cs)

•  Cfinder(Findsclusters–densegroupofnodes)•  NetworkBLAST(Comparesmul4plenetworkstoinfercomplexes&paths)

PPIPredic-onUsingMicroarrayData•  Co‐expressionconcept

•  Correla4onCoefficient»  SIMoNE(Sta4s4calInferenceforModularNetworks)‐R

•  MutualInforma4on»  ReferenceNetworks»  ARACNE(AlgorithmforReconstruc4onofAccurateCellular

Networks)–R,geWorkbench»  CLR(ContextLikelihoodofRelatedness)–R»  MRNET(MaximumRelevance/MinimumRedundancy)–R

»  MONET(ModularizedNETworkLearning)‐Cytoscape

•  BayesianNetwork

PPIPredic-onUsingMicroarrayData•  Melanomametastasis

•  83samples

•  Affymetrix•  GEO•  ARACNE•  geWorkbench•  IP3R1,IP3R2,IP3R3,STIM1,ORAI1

GML File

PredictedPPINetwork•  Couldformacomplex•  Couldbefunc4onallyassociated

•  Couldbeinvolvedinasamemetabolicpathway

•  Couldbeinvolvedinaspecificsignaltransduc4onpath•  Falseposi4ve

Visualiza-onandAnalysisUsingCytoscape•  Cytoscape

•  Opensource•  WorksinWindows,Linux,Mac•  Oneofthefirstdevelopedtools•  GreatnumberofPLUGINS

•  Excellenthelpfromcommunity

LiteratureBasedPPIPredic-onUsingCytoscape

RetrievingPPIUsingCytoscape

DataVisualiza-on,Integra-on,Analysis•  ImportARACNEpredictednetwork

•  ImportVisANTretrievednetwork•  Mergeallnetworks

•  Mo4ffinding

NetCirChro(NetworksonCircularChromosomes)‐Citratecycle

B.sub'lisE.coli S.typhi S.aureus

Gram-negative Bacteria Gram-positive Bacteria

ScienceApps@niaid.nih.gov

ThankYou

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