Stochastic simulations of the tetracycline operon.
BACKGROUND
The tetracycline operon is a self-regulated system. It is found naturally in bacteria where it confers resistance to antibiotic tetracycline. Because of the performance of the molecular elements of the tetracycline operon, these elements are widely used as parts of synthetic gene networks where the protein production can be efficiently turned on and off in response to the presence or the absence of tetracycline. In this paper, we investigate the dynamics of the tetracycline operon. To this end, we develop a mathematical model guided by experimental findings. Our model consists of biochemical reactions that capture the biomolecular interactions of this intriguing system. Having in mind that small biological systems are subjects to stochasticity, we use a stochastic algorithm to simulate the tetracycline operon behavior. A sensitivity analysis of two critical parameters embodied this system is also performed providing a useful understanding of the function of this system.


RESULTS
Simulations generate a timeline of biomolecular events that confer resistance to bacteria against tetracycline. We monitor the amounts of intracellular TetR2 and TetA proteins, the two important regulatory and resistance molecules, as a function of intrecellular tetracycline. We find that lack of one of the promoters of the tetracycline operon has no influence on the total behavior of this system inferring that this promoter is not essential for Escherichia coli. Sensitivity analysis with respect to the binding strength of tetracycline to repressor and of repressor to operators suggests that these two parameters play a predominant role in the behavior of the system. The results of the simulations agree well with experimental observations such as tight repression, fast gene expression, induction with tetracycline, and small intracellular TetR2 amounts.


CONCLUSIONS
Computer simulations of the tetracycline operon afford augmented insight into the interplay between its molecular components. They provide useful explanations of how the components and their interactions have evolved to best serve bacteria carrying this operon. Therefore, simulations may assist in designing novel gene network architectures consisting of tetracycline operon components.
Department of Chemical Engineering and Materials Science, University of Minnesota, 421 Washington Ave SE, Minneapolis, MN 55455, USA.
Konstantinos
K
Biliouris
Prodromos
P
Daoutidis
Yiannis N
YN
Kaznessis
D000465:Algorithms; D000900:Anti-Bacterial Agents / Q000378:metabolism / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D004926:Escherichia coli / Q000166:cytology / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D008954:Models, Biological; D009876:Operon / Q000235:genetics*; D014176:Protein Biosynthesis / Q000187:drug effects; D055503:Protein Multimerization / Q000187:drug effects; D020836:Protein Structure, Quaternary; D013269:Stochastic Processes; D013752:Tetracycline / Q000378:metabolism / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects
D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D013752:Tetracycline
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