The use of orthogonal ribosomes in combination with dynamic resource allocation controllers is a promising approach for relieving the negative effects of cellular resource limitations on the modularity of synthetic gene circuits. Here, we develop a detailed mechanistic model of gene expression and resource allocation, which when simplified to a tractable level of complexity, allows the rational design of translational resource allocation controllers. Analysis of this model reveals a fundamental design trade-off: that reducing coupling acts to decrease gene expression. Through a sensitivity analysis of the experimentally tunable controller parameters, we identify how each controller design parameter affects the overall closed-loop behavior of the system, leading to a detailed set of design guidelines for optimally managing this trade-off. On the basis of our designs, we evaluated a number of alternative potential experimental implementations of the proposed system using commonly available biological components. Finally, we show that the controller is capable of dynamically allocating ribosomes as needed to restore modularity in a number of more complex synthetic circuits, such as the repressilator, and activation cascades composed of multiple interacting modules.

中文翻译：

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工程转化资源分配控制器：机理模型，设计指南和潜在的生物学实现

正交核糖体与动态资源分配控制器结合使用是缓解细胞资源限制对合成基因电路模块性的负面影响的有前途的方法。在这里，我们开发了一个详细的基因表达和资源分配机制模型，将其简化为易于处理的复杂程度后，就可以合理设计翻译资源分配控制器。对这种模型的分析揭示了一个基本的设计折衷方案：减少偶联可减少基因表达。通过对实验上可调的控制器参数的敏感性分析，我们确定了每个控制器设计参数如何影响系统的整体闭环行为，从而得出了一套详细的设计准则，以最佳地管理这一折衷方案。根据我们的设计，我们使用常用的生物组件评估了拟议系统的许多替代性潜在实验实现。最后，我们表明该控制器能够根据需要动态分配核糖体，以恢复许多更复杂的合成电路（如再加压器和由多个相互作用模块组成的激活级联）中的模块性。