title: Robustness analysis and behavior discrimination in enzymatic reaction networks.
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 dynamical properties. Our multi-step analysis allows efficient sampling of the parameter space in order to define feasible regions in which the model exhibits imposed or experimentally observed behaviors. In a first step, an algorithmic methodology involving sensitivity analysis is conducted to determine bifurcation thresholds for a limited number of model parameters or initial conditions. In a second step, this boundary detection is supplemented by a global robustness analysis, 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 switching activity between activation or inhibition of MMP2 production. Further implication of our approach is illustrated by demonstrating and analyzing the possible existence of oscillatory behaviors when considering an extended open configuration of the enzymatic network. Notably, we construct bifurcation diagrams that specify key parameters values controlling the co-existence of stable steady and non-steady oscillatory proteolytic dynamics.
authors: UJF-Grenoble 1, CNRS, Laboratoire VERIMAG UMR 5104, 2, Gières, France. Alexandre.Donze@imag.fr
authors: Alexandre
authors: A
authors: Donzé
authors: Eric
authors: E
authors: Fanchon
authors: Lucie Martine
authors: LM
authors: Gattepaille
authors: Oded
authors: O
authors: Maler
authors: Philippe
authors: P
authors: Tracqui
mesh_terms: D000465:Algorithms; D001671:Biochemistry / Q000379:methods*; D002468:Cell Physiological Phenomena; D004798:Enzymes / Q000737:chemistry*; D053511:Matrix Metalloproteinase 14 / Q000737:chemistry; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D008954:Models, Biological; D015233:Models, Statistical; D009010:Monte Carlo Method; D009991:Oscillometry; D049490:Systems Biology; D013997:Time Factors; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism
chemical_list: D004798:Enzymes; D019716:Tissue Inhibitor of Metalloproteinase-2; D020778:Matrix Metalloproteinase 2; D053511:Matrix Metalloproteinase 14