Optimization-based synthesis of stochastic biocircuits with statistical specifications
Optimization-based synthesis of stochastic biocircuits with statistical specifications
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DOI：
10.1098/rsif.2017.0709
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发表时间：
2018-01-01
影响因子：
3.9
通讯作者：
Hori, Yutaka
中科院分区：
文献类型：
--
作者：
Sakurai, Yuta;Hori, Yutaka
模型引导设计已经成为合成生物学中工程生物分子电路的标准方法。然而，生物分子反应的随机性在设计过程中往往被忽视。因此，细胞-细胞异质性导致生物电路行为与模型预测的意外偏差，并需要额外的设计-构建-测试循环迭代。为了提高随机生物电路的设计过程中，本文提出了一个计算框架，系统地指定使用well-definedmetrics的统计和设计高度异质性的生物电路的基础上的规格的固有噪声的水平。具体来说，我们使用人口分布的描述性统计作为一个直观的规范语言的随机生物电路和开发一个基于优化的计算工具，探索满足设计要求的参数配置。灵敏度分析方法也进行，以确保对外来扰动的生物电路设计的鲁棒性。这些设计工具是用凸优化程序来制定的，以实现对统计数据的严格和有效的量化。我们证明了这些功能，通过设计一个随机的负反馈生物电路，满足多个统计约束，并进行深入研究的噪声传播和负反馈途径的监管。
Model-guided design has become a standard approach to engineering biomolecular circuits in synthetic biology. However, the stochastic nature of biomolecular reactions is often overlooked in the design process. As a result, cell-cell heterogeneity causes unexpected deviation of biocircuit behaviours from model predictions and requires additional iterations of design-buildtest cycles. To enhance the design process of stochastic biocircuits, this paper presents a computational framework to systematically specify the level of intrinsic noise usingwell-definedmetrics of statistics and design highly heterogeneous biocircuits based on the specifications. Specifically, we use descriptive statistics of population distributions as an intuitive specification language of stochastic biocircuits and develop an optimization-based computational tool that explores parameter configurations satisfying design requirements. Sensitivity analysis methods are also performed to ensure the robustness of a biocircuit design against extrinsic perturbations. These design tools are formulated with convex optimization programs to enable rigorous and efficient quantification of the statistics. We demonstrate these features by designing a stochastic negative feedback biocircuit that satisfies multiple statistical constraints and perform an in-depth study of noise propagation and regulation in negative feedback pathways.