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AnalysisofProteinProtein InteractionNetworks

HarshavardhanKhare

Biocrystallographylab. Sr.No.08071

Contents

Aim Introduction Basicconcepts Methods Applications References

Aim

Complexmolecule

Tosimulatecomplex biologicalsystems Whynetworkapproach?

Biologicalsystemsare verycomplex. Simulationatatomicor molecularlevelisvery muchtimeconsumingand complicated. Abstractionofentitiesis needed.

Abstraction

Aim(contd...)

Applicationsandexpectedendresults

Drugdiscovery Predictingcausesofdisordersinthebody,ex. Causesofcancer Discoveringindustriallyusefulbiochemical pathways

Introduction

ElementsofProteinProteinInteraction(PPI) Network

Nodes:Proteinmolecules Edges:Interactions/relationsbetweentwoproteins

Directededges Undirectededges

Abstractionofnodesandedges

Allphysicalandchemicalpropertiesarenot considered.

SchematicrepresentationofPPI network

_________________________________________________

YeastPPInetworkrepresentation

PropertiesofPPInetworks

Powerlawdegreedistribution

P(k)k

Where,kdegreeofnodeandconstant thatdependsuponthenetwork.

Probabilityoffindinganodewithgivendegree decreasesexponentiallywiththedegreeofthe node.

PropertiesofPPInetworks(contd...)

Smallworldproperty

Onanaverageanynodecanbereachedinafew steps(usually4to5). Resistancetofailureondeletionofsomenodes and/oredges i.e.Ondeletionofsomenodesandedgesthe remainingfragmentsofthenetworkfulfilthebasic functionsoftheorganism.

Robustness

PropertiesofPPInetworks(contd...)

Herarchicalmodel

Largeclusteringcoefficient

Ci=(Numberofedgespresentinneighbourhoodofnodei)/(Numberof maximumpossibleedgesintheneighbourhoodofnodei)

Thisindicateshowmanynodesintheneighbourhoodof nodeiareconnectedtoeachother.

MethodsofanalysingPPInetworks

Withinnetworkanalysis

Detectingmodules(usuallytheyarefunctionally important)inanetwork

Traditionallogic:Thesearehighlyconnectedgroupsof nodesthatareseparatedfromeachotherbyveryfew edges. Weightsweregivenbasedonexperimentalvalidation[1]. Weightsformadrawbacksincetheyinduceabias.

Methods(contd...)

DifinitionofmodulebyRidicchietal[2]
ForasubgraphV G, Strongmoduledefinition: Weakmoduledefinition:
k iin (V ) > kiout (V ) i V

k
iV

in i

(V ) > k iout (V )
iV

Disadvantage:Singlenodecannotbesharedbymorethanone modules.

AlgorithmbyGergelyPallaetal[3]

Assumption:Thekcliquesthatshareatleastk1nodesusually formfunctionalmodulesinPPInetworks. Extractallcliquesthatarenotsubgraphsofanyotherclique. Buildcliquecliqueoverlapmatrix,whererowandcolumns representcliqueswhilematrixelementsrepresentnumberof commonnodesineachpairofcliques.Diagonalelements denotethenumberofnodesofthatclique.

Methods(contd...)

Setcutoff(k)onthenumberof commonnodesinapairof cliques. removeoffdiagonal elementsthatarebelow k1 removediagonalelements thatarebelowk Makeremainingvalues'1'and removedvalues'0'.

Thenewmatrixcanbe traversedtodetectdistinct subgraphsthatformhighly connectedmodules.This agreeswiththeabovestated assumtion.Thesearecalledk cliquecomunities.

Methods(contd...)

Betweennetworkanalysis

Comparisonoftwoormorenetworks

Graphinvarientsasdistinguishingcriteria

Numberofnodes Degreeofeachnode(indegreeaswellasoutdegree) Clusteringcoefficientofeachnode Numberofcyclesofaparticularlength

Methods(contd...)

Mywork:Algorithmbasedonprincpalcomponent analysis

ConsiderPPInetworkwithnnodes. Buildshortesttopologicaldistancematrix. Considerthismatrixasthecovariencematrix.


A B C D E F A 0 1 2 3 2 3 B 1 0 1 2 1 2 C 2 1 0 1 2 3 D 3 2 1 0 1 2 E 2 1 2 1 0 1 F 3 2 3 2 1 0

Methods(contd...)

Findouteigenvaluesandeigenvectorsofthismatrix. Theeigenvectorcorrespondingtomaximumeigenvalue iscalledfirstprincipalcomponent(PC1). Itisthevectoralongwhichthevarianceismaximum. Thisimpliesmaximuminformation. PC1softwosuchnetworkswithsamenumberofnodes canbecomparedbasedondifferencesinlengthsor anglebetweenthem. Ifpossible,themeasuresofinteractionotherthanthe simpletopologicaldistancecanbeused.

Applications

Proteinfunctionpredictionbasedonitsinteractionswithother proteins. Predictionofmetabolicpathwayswhererealexperimentsare diffiult. Predictionofpresenceofnewproteinsbycomparingcomplete networkwithanincompleteone. Todiscovernewbiochemicalpathwaysorreactionsandthe conditionsinwhichtheycanoccur. Predictionofdrugtargetsandpossiblesideeffects. Understandingevolutionaryrelationshipbetweendifferent organismsbasedonhowtheirmetabolismworks.

References
1. 'Detectionoffunctionalmodulesfromproteininteractionnetworks,Proteins 54(1):4957,2004',PereiraLealetal 2. 'Definingandidentifyingcommunitiesinnetworks',RadicchiF,CastellanoC, CecconiF,LoretoV,ParisiD;(2004)ProcNatlAcadSciUSA101:2658 2663 3. 'Uncoveringtheoverlappingcommunitystructureofcomplexnetworksin natureandsociety',GergelyPalla,ImreDerenyi,IllesFarkas1&Tamas Vicsek1;Vol435|9June2005|doi:10.1038/nature03607 4. 'Interactiongenerality,ameasurementtoassessthereliabilityofaprotein proteininteraction',Saitoetal.,NAR,30:11631168,2002

ThankYou!