Simulation of Prokaryotic Genetic Circuits

Abstract

Biochemical and genetic approaches have identified the molecular mechanisms of many genetic reactions, particularly in bacteria. Now a comparably detailed understanding is needed of how groupings of genes and related protein reactions interact to orchestrate cellular functions over the cell cycle, to implement preprogrammed cellular development, or to dynamically change a cell's processes and structures in response to environmental signals. Simulations using realistic, molecular-level models of genetic mechanisms and of signal transduction networks are needed to analyze dynamic behavior of multigene systems, to predict behavior of mutant circuits, and to identify the design principles applicable to design of genetic regulatory circuits. When the underlying design rules for regulatory circuits are understood, it will be far easier to recognize common circuit motifs, to identify functions of individual proteins in regulation, and to redesign circuits for altered functions.

Regulation of Gene Expression in Flux Balance Models of Metabolism

“…The time constants characterizing transcriptional regulation are generally on the order of a few minutes or slower (Zubay, 1973;Rivett, 1986;McAdams & Arkin, 1998), which are slower than the time constants associated with metabolism. Therefore, the FBA generation of time pro"les for dynamic cellular behavior may be integrated with a set of transcriptional regulatory rules which are represented by Boolean logic equations.…”

“…Regulatory modeling is also bene"cial to the "eld of metabolic engineering. Using metabolic control analysis, it has been demonstrated that control of biosynthetic #uxes depends on multiple enzymes (Fell, 1998;McAdams & Arkin, 1998). The engineering of cell regulation, rather than of the expression of several related genes, may be a more e$cient use of an organism's metabolism to produce a desired product.…”

Modeling Transcriptional Control in Gene Networks—Methods, Recent Results, and Future Directions

“…For prokaryotic regulatory systems, a significant number of specific models exist, because the greater simplicity and lack of differentiation of prokaryotic cells makes it somewhat easier to delineate macromolecular interactions and rates of processes. For example, the lytic vs lysogenic decision circuit for λ phage integrated in the E. coli chromosome, which is the most thoroughly studied genetic switch (Meyers and Friedland, 1984;Ptashne, 1992), has been modeled in detail as discussed above McAdams and Arkin, 1998). Experimentally based estimates for all model parameter values have been developed.…”

Qualitative simulation of genetic regulatory networks using piecewise-linear models

“…Mathematical models allow networks of interactions to be described in a precise and unambiguous manner, while a large variety of analysis and simulation techniques exists to systematically derive behavior predictions from the models. The application of formal methods, especially when supported by computer tools, may lead to a comprehension of the structure and functioning of large and complex networks of interactions that cannot be obtained through intuitive approaches alone [18,44].…”