Optimization of Time-Course Experiments for Kinetic Model Discrimination 英文参考文献.docVIP

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Optimization of Time-Course Experiments for Kinetic Model Discrimination 英文参考文献.doc

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Optimization of Time-Course Experiments for Kinetic Model Discrimination 英文参考文献

OptimizationofTime-CourseExperimentsforKinetic ModelDiscrimination NunoF.Lages1,2,CarlosCordeiro1,MartaSousaSilva1,AnaPoncesFreire1,Anto′nioE.N.Ferreira1* 1Centro de Qu?′mica e Bioqu?′mica, Departamento de Qu?′mica e Bioqu?′mica, Faculdade de Cie?ncias da Universidade de Lisboa, Lisboa, Portugal, 2Department of Pharmacology,GreenCenterforSystemsBiology,UniversityofTexasSouthwesternMedicalCenter,Dallas,Texas,UnitedStatesofAmerica Abstract Systemsbiologyreliesheavilyontheconstructionofquantitativemodelsofbiochemicalnetworks.Thesemodelsmusthave predictivepowertohelpunveilingtheunderlyingmolecularmechanismsofcellularphysiology,butitisalsoparamount that they are consistent with the data resulting from key experiments. Often, it is possible to find several models that describethedataequallywell,butprovidesignificantlydifferentquantitativepredictionsregardingparticularvariablesof thenetwork.Inthosecases,oneisfacedwithaproblemofmodeldiscrimination,theprocedureofrejectinginappropriate modelsfromasetofcandidatesinordertoelectoneasthebestmodeltouseforprediction.Inthiswork,amethodis proposedtooptimizethedesignofenzymekineticassayswiththegoalofselectingamodelamongasetofcandidates.We focusonmodelswithsystemsofordinarydifferentialequationsastheunderlyingmathematicaldescription.Themethod providesadesignwhereanextensionoftheKullback-Leiblerdistance,computedoverthetimecoursespredictedbythe models,ismaximized.Giventheasymmetricnaturethismeasure,ageneralizeddifferentialevolutionalgorithmformulti- objectiveoptimizationproblemswasused.ThekineticsofyeastglyoxalaseI(EC)waschosenasadifficulttestcaseto evaluatethemethod.Althoughasingle-substratekineticmodelisusuallyconsidered,atwo-substratemechanismhasalso been proposed for this enzyme. We designed an experiment capable of discriminating between the two models by optimizing the initial substrate concentrations of glyoxalase I, in the presence of the subsequent pathway enzyme, glyoxalaseII(EC).Thisdiscriminatoryexperimentwasconductedinthela