Modeling and simulation of nitrogen regulation in Corynebacterium glutamicum

Modeling the dynamic behaviour of biochemical systems at a molecular level aims at understanding and predicting the interactions of macromolecules inside the cell. Models of small subsystems based on differential equations not only prepare the way for the long-term goal of understanding a whole cell, but are inherently valuable due to their ability to predict the behaviour of the subsystem for varying external conditions or parameters. Nitrogen supply is essential for prokaryotes, thus the nitrogen uptake is an interesting target for model building. The goal is to provide new information about the interactions of the relevant proteins by performing various simulations.A model based on piecewise linear differential equations is formulated for the nitrogen uptake in Corynebacterium glutamicum. We theoretically derive a model for biochemical networks and introduce a general method for the parameter estimation which is also applicable in the case of very short time series. This approach is applied to a special system concerning the nitrogen uptake using Western blot experiments. The equations are set up for the main components of this system, the optimization problem for parameter estimation is formulated and solved, and simulations for the evaluation of the model as well as for predictions are carried out.We show that model building based on differential equations can also, when only a few measurements are performed, lead to a satisfactory model which provides valuable insights into the way it’s network components function. For example, we are able to make predictions about the maximal value of the time course as well as the steady-state level of the signal transduction protein GlnK in case of restricted activity of the proteases when considering the transition of nitrogen starvation to nitrogen excess or vice versa.