Evolutionary Trace for Prediction and Redesign of Protein Functional Sites

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1、Chapter3EvolutionaryTraceforPredictionandRedesignofProteinFunctionalSitesAngelaWilkins,SerkanErdin,RhonaldLua,andOlivierLichtargeAbstractTheevolutionarytrace(ET)isthesinglemostvalidatedapproachtoidentifyproteinfunctionaldeterminantsandtotargetmutationalanalysis,proteinengineeringandd

2、rugdesigntothemostrelevantsitesofaprotein.Itappliestotheentireproteome;itspredictionscomewithareliabilityscore;anditsresultstypicallyreachsignificanceinmostproteinfamilieswith20ormoresequencehomologs.Inordertoidentifyfunctionalhotspots,ETscansamultiplesequencealignmentforresiduevariat

3、ionsthatcorrelatewithmajorevolutionarydivergences.Incasestudiesthisenablestheselectiveseparation,recoding,ormimicryoffunctionalsitesand,onalargescale,thisenablesspecificfunctionpredictionsbasedonmotifsbuiltfromselectET-identifiedresidues.ETisthereforeanaccurate,scalableandefficientmetho

4、dtoidentifythemoleculardeterminantsofproteinfunctionandtodirecttheirrationalperturbationfortherapeuticpurposes.PublicETserversarelocatedat:http://mammoth.bcm.tmc.edu/.Keywords:Evolutionarytrace,Proteindesign,Proteinengineering,Functionannotation,Phylogenomics,Protein–proteininteracti

5、on1.Introduction1.1.BasicsTheevolutionarytrace(ET)isaphylogenomicmethodtoidentifyofEvolutionaryTrace:importantaminoacidsinproteinsequences.Theapproachcon-PhylogeneticResidueceptuallymimicsexperimentalmutationalscanning:WhereasinVariationthelaboratoryasequenceresidueisdeemedimportantw

6、henitsmutationchangestheresponseofanassay,ETinfersthataresidueisimportantwhenitsvariationsduringevolutioncorrelatewithmajordivergences(1,2).Thus,ETaimstomeasuretheimpactofaresiduenotbyitsconservationorthroughitsco-variations,butratherbyitsassociatedevolutionarychangesandthefunctional

7、perturbationsandadaptationthattheypresumablyrepresent.TheETapproachtomeasurethecorrelationbetweenresidueandphylogeneticvariationsisstillunderrefinement.ButthebasicRiccardoBaron(ed.),ComputationalDrugDiscoveryandDesign,MethodsinMolecularBiology,vol.819,DOI10.1007/978-1-61779-465-0_3,#S

8、pringerScien