Control Theory Concepts for Modeling Uncertainty in Enzyme Kinetics of Biochemical Networks

ABSTRACT Analysis of the dynamic and steady-state properties of biochemical networks hinge on information about the parameters of enzyme kinetics. The lack of experimental data characterizing enzyme activities and kinetics along with the associated uncertainties impede the development of kinetic models, and researchers commonly use Monte Carlo sampling to explore the parameter space. However, the sampling of parameter spaces is a computationally expensive task for larger biochemical networks. To address this issue, we exploit the fact that reaction rates of biochemical reactions and network responses can be expressed as a function of displacements from thermodynamic equilibrium of elementary reaction steps and concentrations of free enzymes and their intermediary complexes. For a set of kinetic mechanisms ubiquitously found in biochemistry, we express kinetic responses of enzymes to changes in network metabolite concentrations through these quantities both analytically and schematically. The tailor-made sampling of these quantities allows for characterizing the missing kinetic parameters and accelerating the efforts towards building genome-scale kinetic metabolic models.