Realizing “integral control” in living cells: How to overcome leaky integration due to dilution?
Realizing “integral control” in living cells: How to overcome leaky integration due to dilution?
复制标题
实现活细胞的“积分控制”：如何克服稀释导致的积分泄漏？
DOI：
10.1101/141051
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发表时间：
2017
期刊：
影响因子：
--
通讯作者：
Domitilla Del Vecchio
中科院分区：
文献类型：
--
作者：
Y. Qian;Domitilla Del Vecchio
具有积分作用的反馈控制系统具有完美地达到恒定设定点和拒绝恒定干扰的独特能力。由于这些特性，它们在工程系统中无处不在，并且经常在实现稳态和适应的自然生物系统中发现。最近，在合成生物学领域，人们越来越关注积分控制器的实现，以提高电路的鲁棒性和严格调节基因表达。虽然已经提出了一些电路设计，它们的功能往往取决于关键的假设，即控制器中的物质不稀释，因为稀释打破了控制器的集成结构，并导致“泄漏集成”。虽然这种假设在无细胞系统中得到满足，但在活细胞中的实施方式中不满足，其中细胞生长和分裂决定物种稀释。在这份报告中，我们抽象以前提出的生物分子积分控制器的设计成两个理想的积分控制图案（IICM），I型和II型。在此基础上，我们从数学上演示了如何在控制器反应和稀释之间设计一个时间尺度分离，我们可以获得准积分控制基序（qICM），即使在稀释的情况下，也可以恢复几乎完美的适应。与先前的假设相反，我们的研究结果表明，单独实施快速积分动作可能不足以恢复自适应特性。我们的研究结果是基于一个一般的动态模型的“植物”和“控制器”，我们提供了易于检查的代数条件几乎完美的适应。这些条件可以作为设计的指导。在这里，我们提出了两个双分子实现的qICM都设计达到适应基因表达的波动在细胞资源。
Feedback control systems with integral action have the unique ability to perfectly reach constant set-points and to reject constant disturbances. Due to these properties, they are ubiquitous in engineering systems and frequently found in natural biological systems that achieve homeostasis and adaptation. Recently, there has been increasing interest in realizing integral controllers in the synthetic biology community as a way to improve robustness of circuits and tightly regulate gene expression. Although a number of circuit designs have been proposed, their functionality often hinges on the critical assumption that species in the controller do not dilute, since dilution breaks the controller integration structure and leads to “leaky integration”. While this assumption is satisfied in cell-free systems, it is not met in implementations in living cells, where cell growth and division dictates species dilution. In this report, we abstract previously proposed designs of biomolecular integral controllers into two ideal integral control motifs (IICM), type I and type II. Based on these, we mathematically demonstrate how engineering a time-scale separation between the controller reactions and dilution, we can obtain quasi-integral control motifs (qICM) that recover almost perfect adaptation even in the presence of dilution. Contrary to previous hypothesis, our results show that implementing a fast integral action alone may not be sufficient to recover the adaptation property. Our results are based on a general dynamical model of a “plant” and a “controller” for which we provide easy-to-check algebraic conditions for almost perfect adaptation. These conditions can be used as guidance for design. Here, we propose two bimolecular implementations of qICMs both designed to reach adaptation of gene expression to fluctuations in cellular resources.
影响因子：
10.5
作者：
Massé, E;Escorcia, FE;Gottesman, S
通讯作者：
Gottesman, S