Robustness Analysis and Behavior Discrimination in Enzymatic Reaction Networks 英文参考文献.docVIP

RobustnessAnalysisandBehaviorDiscriminationin EnzymaticReactionNetworks AlexandreDonze′1*,EricFanchon2,LucieMartineGattepaille2¤,OdedMaler1,PhilippeTracqui2* 1UJF-Grenoble1,CNRS,LaboratoireVERIMAGUMR5104,2,Gie`res,France,2UJF-Grenoble1,CNRS,LaboratoireTIMC-IMAGUMR5525,DyCTiMandBCMteams,Faculte′ deMe′decinedeGrenobleetIn3S,Grenoble,France Abstract Characterizing the behavior and robustness of enzymatic networks with numerous variables and unknown parameter values is a major challenge in biology, especially when some enzymes have counter-intuitive properties or switch-like behavior between activation and inhibition. In this paper, we propose new methodological and tool-supported contributions, based on the intuitive formalism of temporal logic, to express in a rigorous manner arbitrarily complex dynamicalproperties.Ourmulti-stepanalysisallowsefficientsamplingoftheparameterspaceinordertodefinefeasible regions in which the model exhibits imposed or experimentally observed behaviors. In a first step, an algorithmic methodologyinvolvingsensitivityanalysisisconductedtodeterminebifurcationthresholdsforalimitednumberofmodel parametersorinitialconditions.Inasecondstep,thisboundarydetectionissupplementedbyaglobalrobustnessanalysis, based on quasi-Monte Carlo approach that takes into account all model parameters. We apply this method to a well- documented enzymatic reaction network describing collagen proteolysis by matrix metalloproteinase MMP2 and membrane type 1 metalloproteinase (MT1-MMP) in the presence of tissue inhibitor of metalloproteinase TIMP2. For this model, our method provides an extended analysis and quantification of network robustness toward paradoxical TIMP2 switchingactivitybetweenactivationorinhibitionofMMP2production.Furtherimplicationofourapproachisillustratedby demonstrating and analyzing the possible existence of oscillatory behaviors when considering an extended open configuration of the enzymatic network. Notably, we construct bifurcation diagrams