Automated Leak Analysis of Nucleic Acid Circuits.
Automated Leak Analysis of Nucleic Acid Circuits.
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DOI：
10.1021/acssynbio.2c00084
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发表时间：
2022-05
影响因子：
4.7
通讯作者：
Iuliia Zarubiieva;Carlo Spaccasassi;V. Kulkarni;Andrew Phillips
中科院分区：
文献类型：
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作者：
Iuliia Zarubiieva;Carlo Spaccasassi;V. Kulkarni;Andrew Phillips
核酸是一种功能强大的工程材料，可用于在纳米级实现广泛的计算电路，在高精度生物传感，诊断和治疗方面具有潜在的应用。然而，核酸回路易于泄漏，这是由核酸链之间的非预期置换相互作用引起的。这种泄漏可能会随着电路尺寸的增长而增长，缓解起来很有挑战性，并且可能会严重损害电路行为。虽然已经提出了几种技术来部分减轻泄漏，但用于设计新的泄漏减轻策略并比较其对电路行为的有效性的计算方法是有限的。在这里，我们提出了一种用于核酸回路的自动泄漏分析的一般方法，称为DSD泄漏。我们的方法扩展了Visual DSD语言的逻辑编程功能，开发用于核酸电路的设计和分析，具有用于泄漏生成的谓词，泄漏反应枚举算法和排除低概率泄漏反应的谓词。我们使用我们的方法来识别影响控制电路性能的关键泄漏反应，并通过自动生成泄漏反应来分析泄漏缓解策略。最后，我们设计了新的控制电路，大大减少了泄漏，包括一个复杂的比例积分控制器电路，这反过来又可以作为未来电路的积木。通过将我们的方法整合到开源核酸电路设计工具中，我们能够对广泛的电路进行泄漏分析，这是促进稳健和可扩展的核酸电路设计的重要一步。
Nucleic acids are a powerful engineering material that can be used to implement a broad range of computational circuits at the nanoscale, with potential applications in high-precision biosensing, diagnostics, and therapeutics. However, nucleic acid circuits are prone to leaks, which result from unintended displacement interactions between nucleic acid strands. Such leaks can grow combinatorially with circuit size, are challenging to mitigate, and can significantly compromise circuit behavior. While several techniques have been proposed to partially mitigate leaks, computational methods for designing new leak mitigation strategies and comparing their effectiveness on circuit behavior are limited. Here we present a general method for the automated leak analysis of nucleic acid circuits, referred to as DSD Leaks. Our method extends the logic programming functionality of the Visual DSD language, developed for the design and analysis of nucleic acid circuits, with predicates for leak generation, a leak reaction enumeration algorithm, and predicates to exclude low probability leak reactions. We use our method to identify the critical leak reactions affecting the performance of control circuits, and to analyze leak mitigation strategies by automatically generating leak reactions. Finally, we design new control circuits with substantially reduced leakage including a sophisticated proportional-integral controller circuit, which can in turn serve as building blocks for future circuits. By integrating our method within an open-source nucleic acid circuit design tool, we enable the leak analysis of a broad range of circuits, as an important step toward facilitating robust and scalable nucleic acid circuit design.