Author:
Biliouris Konstantinos,Daoutidis Prodromos,Kaznessis Yiannis N
Abstract
Abstract
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.
Publisher
Springer Science and Business Media LLC
Subject
Applied Mathematics,Computer Science Applications,Molecular Biology,Modeling and Simulation,Structural Biology
Reference65 articles.
1. Wong P, Gladney S, Keasling J: Mathematical model of the lac operon: inducer exclusion, catabolite repression, and diauxic growth on glucose and lactose. Biotechnology progress. 1997, 13 (2):
2. Stamatakis M, Mantzaris N: Comparison of Deterministic and Stochastic Models of the lac Operon Genetic Network. Biophysical Journal. 2009, 96 (3): 887-906. 10.1016/j.bpj.2008.10.028
3. Xiu Z, Chang Z, Zeng A: Nonlinear dynamics of regulation of bacterial trp operon: model analysis of integrated effects of repression, feedback inhibition, and attenuation. Biotechnology progress. 2002, 18 (4): 686-693. 10.1021/bp020052n
4. Elowitz M, Leibler S: A synthetic oscillatory network of transcriptional regulators. Nature. 2000, 403 (6767): 335-338. 10.1038/35002125
5. Tuttle L, Salis H, Tomshine J, Kaznessis Y: Model-driven designs of an oscillating gene network. Biophysical journal. 2005, 89 (6): 3873-3883. 10.1529/biophysj.105.064204
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