Understanding regulatory properties of complex biological systems can be improved through the application of mathematical modeling approach

One of the main aims of modern biological science is to understand regulatory mechanisms which determine response of any biological system to any perturbation of external condition. To cope with the task we can apply to the system either experimental examination or mathematical modeling approach. Each way has own advantages and disadvantages in dependence on the system under consideration. The case is that if we consider the system which was intensively studied before and, consequently, its stoichiometry is well known and kinetics of partial reactions is quantitatively characterized, then development of mathematical model of the system allows us to describe (and sometimes to predict) response of the system to the perturbation of external parameters. Here, we consider two complex biological systems and show the way in following which mathematical modeling helps us to understand regulatory properties of each system. The method of quantification of the regulatory properties - Metabolic Control Analysis (MCA), was developed in [1-4]. In the framework of MCA control and elasticity coefficients were determined to describe system and local (each separate reaction) regulatory properties, respectively.

Applying mathematical modeling and MCA approaches to the following biological systems:

1) mitochondria respiring on succinate;

2) pathway of signal transduction initiated with epidermal growth factor (EGF).

We found that

1) to minimize superoxide production and maximize oxygen consumption in mitochondria there are only two possible ways: to increase concentration of ATP/ADP translocator or to decrease concentration of succinate ubiquinone reductase;

2) experimentally observed pronounced maximum in the time course of tyrosine phosphorylation of EGF receptor and in activation of some its target protein can be accounted for without any assumptions, requiring receptor mediated activation of specific tyrosine phosphotase.

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3. Westerhoff, H.V., Van Dam, K. Thermodynamics and Control of Biological Free Energy transduction, Elsevier, Amsterdam, 1987.
4. Demin, O.V., Kholodenko., B.N., Westerhoff, H.V. J. Phys. Chem. in press.