SHF: Small: Error Correction for Biomolecular Computations

智力优势：纠错是所有类型计算的基本挑战，尤其是分子尺度计算的基本挑战。DNA计算是以DNA作为计算硬件的分子计算。目前的DNA计算方法被高错误率所困扰。错误处理技术是在实验室中实现可靠的DNA计算的关键。事实上，看看DNA计算领域的成功，就能清楚地证明错误处理技术所起的作用。加州理工学院的Winfree小组最近成功地在实验室实现了布尔DNA电路，其复杂性令人印象深刻，他们使用了一种被称为跷跷板门的化学逻辑门。他们的工作使用了两种类型的纠错(i)电路网络级别的内置信号恢复，以及（ii）箝位，DNA门设计级别的错误抑制方法。纠错仍然是进一步扩展这些分子计算的最大挑战。一种特别困难的错误类型是泄漏，即使在没有输入信号的情况下，最终也会产生输出信号。由于泄漏，DNA电路中的逻辑门通常只能在有限的时间间隔内正确工作，然后提供错误的输出。提出的工作的中心目标是对泄漏进行错误纠正的方法。在DNA计算中。拟议的工作将开发新的网络级设计和门级设计，使用一系列创新技术、阴影网络和错误调制门来抑制泄漏。一个关键的应用是DNA放大器，它以一定浓度的DNA链作为输入，并产生输出信号DNA链。DNA放大器是有漏洞的，即使在没有输入的情况下也能产生信号DNA，尽管速度较慢。信号和噪声之间的差异决定了放大器的灵敏度。无酶DNA指数放大器具有高泄漏率，这限制了它们检测少量信号的灵敏度。本提案描述了抑制此类放大器泄漏的网络级设计和门级设计。作为一个具体且具有挑战性的测试案例，指数交叉催化DNA放大器的错误抑制将被证明是一个主要目标。将使用建模、软件仿真和实验测试的良好平衡组合来验证纠错方法。提出的错误处理技术被建模为化学反应网络，然后对这种网络进行模拟。这个指数放大器是基于跷跷板门，因此很好地模拟为一个化学反应网络。更广泛的影响：提案中概述的设计是模块化的，允许各种纠错组件几乎像黑盒子一样使用。错误抑制技术是通用的，并转化为各种各样的其他DNA放大器设计和DNA计算应用涉及信号的放大或恢复。在设计阶段，系统地识别实验DNA系统中可能出现的错误以及抑制和/或纠正这些错误的方法的能力对于设计可扩展和复杂的DNA纳米系统至关重要。作为一项教育努力，我们计划开设一门高级本科和研究生初级课程，将错误处理作为设计DNA系统的一个组成部分来教授。本课程将向学生介绍建模工具和序列设计工具。学生将为一些常见的DNA系统（如放大器、振荡器和开关）开发纠错方案。然后，他们对他们的技术进行建模，在模拟中效果最好的技术将有机会在实验室中实施。

Intellectual Merit: Error-correction is a fundamental challenge for all types of computation, and it is a particularly essential challenge for molecular-scale computation. DNA computation is molecular computation using DNA as the computational hardware. Current methods for DNA computations are beset by a high error rate. Error-handling techniques are the key to achieving robust DNA computation in the laboratory. Indeed, a look at the successes in the field of DNA computation clearly demonstrates the role played by error-handling techniques. Winfree's group at Caltech recently made successful laboratory implementations of Boolean DNA circuits of impressive complexity, using a type of chemical logical gate known as a seesaw gate. Their work made use of two types of error-correction (i) inbuilt signal restoration at the circuit network level, and (ii)clamps, a method of error-suppression at the DNA gate design level. Error-correction remains the single largest challenge to further scaling these molecular computations. A particularly difficult type of error is leaks where an output signal is eventually produced even in the absence of an input signal. Due to leaks, logical gates in DNA circuits generally only correctly operate for a limited time interval, and afterwards provide erroneous outputs. The central goal of the proposed work is methods for error-correction of ?leaks? in DNA computations. Proposed work will develop novel network level designs and gate level designs that suppress leaks using a family of innovative techniques, shadow networks and error-modulation gates. A key application is to DNA amplifiers, which take as input a DNA strand at some concentration and produce an output signal DNA strand. DNA amplifiers are leaky, producing signal DNA even in the absence of input, albeit at a slower rate. The difference between signal and noise decides the sensitivity of an amplifier. Enzyme-free DNA exponential amplifiers have high leak rates that limit their sensitivity to detecting small amounts of signal. This proposal describes both network level designs and gate level designs that suppress leaks in such amplifiers. As a concrete and challenging test case, error-suppression in an exponential cross-catalytic DNA amplifier will be demonstrated as a major goal. A well-balanced combination of modeling, software simulation, and experimental tests to verify the error-correction methods will be used. Proposed error-handling techniques are modeled as chemical reaction networks and such networks are then simulated. This exponential amplifier is based on seesaw gates and is hence well modeled as a chemical reaction network.Broader Impact: The designs outlined in the proposal are modular, allowing the various error-correcting components to be used almost as black boxes. The error-suppression techniques are general and translate to a wide variety of other DNA amplifier designs and DNA computing applications involving amplification or restoration of a signal. An ability to systematically identify, at the design stage, possible errors in experimental DNA systems and methods to suppress and/or correct them is essential for designing scalable and intricate DNA nanosystems. As an educational effort, an advanced undergraduate and beginning graduate level course is planned that teaches error-handling as an integral part of designing DNA systems. The course will introduce students to modeling tools and sequence design tools. The students will develop error-correcting schemes for some common DNA systems like amplifiers, oscillators and switches. They then model their techniques and the ones that work best in simulation will be given an opportunity to implement them in the laboratory.