Stochastic simulations of the tetracycline operon.
Stochastic simulations of the tetracycline operon.
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DOI：
10.1186/1752-0509-5-9
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发表时间：
2011-01-19
影响因子：
--
通讯作者：
Kaznessis YN
中科院分区：
文献类型：
--
作者：
Biliouris K;Daoutidis P;Kaznessis YN
四环素操纵子是一个自我调节系统。它天然存在于细菌中，它赋予对抗生素四环素的抗性。由于四环素操纵子的分子元件的性能，这些元件被广泛用作合成基因网络的一部分，其中蛋白质生产可以响应于四环素的存在或不存在而有效地打开和关闭。本文研究了四环素操纵子的动力学。为此，我们开发了一个数学模型的实验结果为指导。我们的模型由捕获这个有趣系统的生物分子相互作用的生化反应组成。考虑到小的生物系统是随机的，我们使用随机算法来模拟四环素操纵子的行为。还对该系统的两个关键参数进行了灵敏度分析，从而对该系统的功能有了有益的了解。模拟产生生物分子事件的时间轴，这些事件赋予细菌对四环素的抗性。我们监测细胞内的TetR2和TetA蛋白，两个重要的调节和耐药分子，作为一个功能的intrecellular四环素的量。我们发现，四环素操纵子的启动子之一的缺乏对该系统的总体行为没有影响，推断该启动子对大肠杆菌不是必需的。灵敏度分析表明，四环素的阻遏物和阻遏物的运营商的结合强度，这两个参数发挥主导作用的系统的行为。模拟结果与实验观察结果吻合良好，如紧密阻遏，快速基因表达，四环素诱导，和小细胞内TetR2量。四环素操纵子的计算机模拟增强了对其分子组分之间相互作用的了解。它们提供了有用的解释，说明这些成分及其相互作用如何进化，以最好地为携带这种操纵子的细菌服务。因此，模拟可能有助于设计由四环素操纵子组件组成的新型基因网络架构。
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. 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. 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.
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