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Open Access Research article

Modeling metabolic networks in C. glutamicum: a comparison of rate laws in combination with various parameter optimization strategies

Andreas Dräger1*, Marcel Kronfeld1*, Michael J Ziller1*, Jochen Supper1, Hannes Planatscher1, Jørgen B Magnus23, Marco Oldiges3, Oliver Kohlbacher1 and Andreas Zell1

Author Affiliations

1 Center for Bioinformatics Tübingen (ZBIT), Wilhelm-Schickard-Institut für Informatik, Sand 1, 72076 Tübingen, Germany

2 NNE Pharmaplan, Siemensstraße 21, 61352 Bad Homburg, Germany

3 Forschungszentrum Jülich, Institut für Biotechnologie 2, 52425 Jülich, Germany

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BMC Systems Biology 2009, 3:5  doi:10.1186/1752-0509-3-5

Published: 14 January 2009

Abstract

Background

To understand the dynamic behavior of cellular systems, mathematical modeling is often necessary and comprises three steps: (1) experimental measurement of participating molecules, (2) assignment of rate laws to each reaction, and (3) parameter calibration with respect to the measurements. In each of these steps the modeler is confronted with a plethora of alternative approaches, e. g., the selection of approximative rate laws in step two as specific equations are often unknown, or the choice of an estimation procedure with its specific settings in step three. This overall process with its numerous choices and the mutual influence between them makes it hard to single out the best modeling approach for a given problem.

Results

We investigate the modeling process using multiple kinetic equations together with various parameter optimization methods for a well-characterized example network, the biosynthesis of valine and leucine in C. glutamicum. For this purpose, we derive seven dynamic models based on generalized mass action, Michaelis-Menten and convenience kinetics as well as the stochastic Langevin equation. In addition, we introduce two modeling approaches for feedback inhibition to the mass action kinetics. The parameters of each model are estimated using eight optimization strategies. To determine the most promising modeling approaches together with the best optimization algorithms, we carry out a two-step benchmark: (1) coarse-grained comparison of the algorithms on all models and (2) fine-grained tuning of the best optimization algorithms and models. To analyze the space of the best parameters found for each model, we apply clustering, variance, and correlation analysis.

Conclusion

A mixed model based on the convenience rate law and the Michaelis-Menten equation, in which all reactions are assumed to be reversible, is the most suitable deterministic modeling approach followed by a reversible generalized mass action kinetics model. A Langevin model is advisable to take stochastic effects into account. To estimate the model parameters, three algorithms are particularly useful: For first attempts the settings-free Tribes algorithm yields valuable results. Particle swarm optimization and differential evolution provide significantly better results with appropriate settings.