Modeling complex cellular systems : from differential equations to constraint-based models

In the beginning of the 20th century, scientists realized the necessity of purifying enzymes to unravel their mechanistic nature. A century and tremendous progresses in the natural sciences later, molecular and systems biology became fundamental pillars of modern biology. Moreover, natural scientists developed an increasing interest in theoretical models. In the first part of my thesis, I present my contribution to the field of studying the dynamics of biological phenomena. I present fundamental issues arising, when neglecting substrate inhibition in kinetic modeling. Furthermore, I describe a model that considers experimental data to simulate the transition of normal proliferating into cellular senescent cells. Since large-scaled models are more comprehensive, they commonly prohibit a mechanistic modeling approach. In order to analyze such models, nevertheless, constraint-based methods proved to be suitable tools. In the second part of my thesis, I contribute three studies to constraint-based modeling. I describe the established concept of elementary flux modes, which resemble non-decomposable and theoretically feasible pathways of metabolic networks. Subsequently, I present the analysis of the nitrogen metabolism network of Chlamydomonas reinhardtii with respect to circadian regulation, which gives rise to about three million elementary flux modes. In the last study, I present a comprehensive work on metabolic costs of amino acid and protein production in Escherichia coli. These costs were manually calculated as well as based on a flux balance analysis of an E. coli genome-scale metabolic model. Both approaches, either dynamic or constraint-based modeling, proved to be suitable strategies to describe biological processes at different levels. Whereas dynamic modeling allowed for a precise description of the temporal behavior of biological species, constraint-based modeling enabled studies, where the complexity of the investigated phenomena prohibits kinetic modeling.


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