CAREER: Engineering Nucleic Acid Devices

加州理工大学皮尔斯实验室提出了一项将理论、计算和实验相结合的研究计划，以推动结构核酸纳米技术领域的发展，开发出严格而稳健的方法来编码核酸序列中的任意机械功能。建模和算法开发项目将解决关键的分析和设计挑战。对伪结生物物理的研究将有助于为配分函数算法创建基于物理的势，并阐明拓扑在用于向自主设备输送催化燃料的实验研究中的“接吻发夹”机制的行为中的作用，以及：-关于使用配分函数信息实现用于优化目标二级结构的亲和力和专一性的高效分层变异算法--关于用于识别和设计包括与自主设备设计相关的亚稳态网络的能量景观的多个特征的方法-以及关于公式化和优化表征设备工程的多目标设计问题，其中多条链必须根据存在的链物种的子集有条件地采用不同的结构。智力价值拟议的研究计划寻求开发分析和设计工具，以极大地提高设计核酸装置的严密性、准确性和自动化水平。这项工作包括物理建模、算法开发、机制设计和实验验证，统一的目标是实现对多种能量环境中微妙特征的操纵，这些环境是具有许多条件稳定状态的设备设计的基础。开发一种实用的催化燃料输送方法，并随后建造一种强大的自主步行器，可以在没有辅助的情况下走数百步，这将是该领域的一项突破。同样，HCR为核酸纳米技术提供了一种新的功能范式，为研究创造了许多有吸引力的途径。广泛影响有朝一日，在纳米尺度上设计自主设备的能力可能会有重要的医疗应用，包括靶向输送有毒药物。在短期内，HCR有可能促进建造多功能和廉价的生物传感器。本科生有机会通过加州理工大学暑期本科生研究奖学金项目充分参与这项跨学科研究。其他大学的研究人员可以免费下载皮尔斯实验室开发的分析和设计软件的源代码。在帕萨迪纳公立学校，62%的学生参加免费或降价餐饮计划，80%以上的学生是代表不足的少数族裔。对于许多学生来说，Jr.教师计划将提供一个难得的机会来考虑追求科学或工程职业的吸引力。

The Pierce Lab at Caltech proposes a research program that combines theoretical, computationaland experimental components to advance the field of structural nucleic acid nanotechnology in developing rigorous and robust methods for encoding arbitrary mechanical function in nucleic acid sequences. Modeling and algorithm development projects will address key analysis and design challenges. The investigation of pseudoknot biophysics will help to create a physically based potential for partition function algorithms and illuminate the role of topology in the behavior of the "kissing hairpin" mechanism under experimental study for catalytic fuel delivery to autonomous devices as well as:-on implementing an efficient hierarchical mutation algorithm for optimizing affinity and specificity for target secondary structures using partition function information-on methods for identifying and designing multiple features of an energy landscape including networks of metastable states relevant to autonomous device design-and on formulating and optimizing the multi-objective design problem that characterizes device engineering, in which multiple strands must conditionally adopt different structures depending on the subsets of strand species that are present.Intellectual MeritThe proposed research program seeks to develop analysis and design tools that will dramatically increase the level of rigor, accuracy, and automation with which nucleic acid devices are engineered. The work encompasses physical modeling, algorithm development, mechanism design, and experimental validation, with the unifying goal of enabling the manipulation of subtle features in the multiple energy landscapes that underlie the design of devices with many conditionally stable states. The development of a practical catalytic fuel delivery method and subsequent construction of a robust autonomous walker that can take hundreds of unassisted steps would represent a breakthrough in the field. Likewise, HCR provides a new functional paradigm for nucleic acid nanotechnology, creating many attractive avenues for investigation.Broader ImpactThe ability to engineer autonomous devices at the nanometer length scale may someday have importantmedical applications including the targeted delivery of toxic drugs. In the nearer term, HCR has the potential to facilitate the construction of versatile and inexpensive biosensors. Undergraduates have the opportunity to participate fully in this interdisciplinary research through the Caltech Summer Undergraduate Research Fellowship program. Researchers at other universities can freely download source code for the analysis and design software developed in the Pierce Lab. At Pasadena public schools, 62% of students participate in free or reduced-price meal programs and more than 80% of students are underrepresented minorities. For many students, the Jr. Teacher program will provide a rare opportunity to consider the attractions of pursuing a career in science or engineering.