To unravel the complex in vivo regulatory interdependences of biochemical networks, experiments with the living organism are absolutely necessary. Stimulus response experiments (SREs) have become increasingly popular in recent years. The response of metabolite concentrations from all major parts of the central metabolism is monitored over time by modern analytical methods, producing several thousand data points. SREs are applied to determine enzyme kinetic parameters and to find unknown enzyme regulatory mechanisms. Owing to the complex regulatory structure of metabolic networks and the amount of measured data, the evaluation of an SRE has to be extensively supported by modelling. If the enzyme regulatory mechanisms are part of the investigation, a large number of models with different enzyme kinetics have to be tested for their ability to reproduce the observed behaviour. In this contribution, a systematic model-building process for data-driven exploratory modelling is introduced with the aim of discovering essential features of the biological system. The process is based on data pre-processing, correlation-based hypothesis generation, automatic model family generation, large-scale model selection and statistical analysis of the best-fitting models followed by an extraction of common features. It is illustrated by the example of the aromatic amino acid synthesis pathway in Escherichia coli. 2006@en

Model selection is concerned with the choice of a mathematical model from a set of candidates that best describes a given set of experimental data. Large families of models arise in the context of structured mechanistic modelling in several application fields. In this situation the model selection problem cannot be solved by brute force testing of all possible models because of the high computational costs. However, more information on the different models of a family is available by their interdependencies, given by generalization or simplification relations. Large-scale model selection algorithms should exploit these relations for navigation in the discrete space of all model candidates. This paper presents a general approach for large-scale model selection by specifying the necessary computational primitives for navigating in large model families. As a non-trivial example it is shown how families of biochemical network models arising from the evaluation of stimulus response experiments are mapped to the general formalism. Finally, a first model selection algorithm based on the mentioned computational primitives is introduced and applied to complex biochemical network experiments. It is based on a load-balancing algorithm by making use of grid computing facilities.

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