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Collaborative Research: FET: Medium: Engineering DNA and RNA computation through simulation, sequence design, and experimental verification

合作研究：FET：中：通过模拟、序列设计和实验验证进行 DNA 和 RNA 计算

基本信息

批准号：
2211792
负责人：
Christopher Thachuk
金额：
$ 42.92万
依托单位：
University of Washington
依托单位国家：
美国
项目类别：
Continuing Grant
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=2211792&HistoricalAwards=false
关键词：
Collaborative Research FET Medium Engineering

项目摘要

Designed nucleic acid sequences (DNA or RNA) can self-assemble into nanoscale structures and devices with promising applications in diagnostics, therapeutics, and nanoscale manufacturing. Strand displacement, where an invader single strand displaces an incumbent strand bound to a complementary substrate, is a key process in dynamic DNA nanotechnology. While DNA strand displacement circuits have proven to be capable of complex computation, they do not interface as naturally to biological systems (e.g., CRISPR) as RNA. Meanwhile, RNA circuits have not achieved the same level of success. This research aims to develop a richer understanding and precise control of hybrid DNA:RNA displacement that may lead to entirely new levels of sophistication in molecular circuits capable of inter-operation with biological systems. A flexible, user-friendly sequence design tool will significantly reduce the barrier to implementation for non-experts. Education and outreach activities will broaden participation in computing and cross-train students in multiple disciplines by reaching across subject boundaries. The investigators will collect experimental data to parameterize new coarse-grained models of DNA-RNA hybrid systems, including Markov chain models capable of rapid in-silico simulation to determine kinetic reaction rates. These hybrid models will also parameterize mismatch creation and repair during displacement making possible the design of strand displacement reactions with precise kinetic control using both DNA and RNA, and thus allowing a natural interface of complex computational cascades with biological signals. A general-purpose DNA and RNA sequence design tool will be developed that focuses on four tasks: algorithmic/efficiency improvements, development of new models to enhance the behaviors expressible as constraints, integration with existing tools, and the design and experimental demonstration of a hybrid DNA:RNA displacement system that implements a self-stabilizing clock, capable of producing RNA strands at a fixed period.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

设计的核酸序列（DNA或RNA）可以自组装成纳米级结构和设备，在诊断，治疗和纳米级制造中具有广阔的应用前景。链置换是动态DNA纳米技术中的一个关键过程，其中入侵者单链置换与互补底物结合的现任链。虽然DNA链置换电路已被证明能够进行复杂的计算，但它们并不自然地与生物系统（例如，CRISPR）作为RNA。与此同时，RNA电路还没有达到同样的成功水平。这项研究旨在对杂交DNA：RNA置换进行更丰富的理解和精确的控制，这可能会导致能够与生物系统相互作用的分子电路的全新复杂程度。一个灵活的、用户友好的序列设计工具将大大减少非专家实施的障碍。教育和外联活动将扩大对计算的参与，并通过跨越学科界限对学生进行多学科交叉培训。研究人员将收集实验数据，以参数化DNA-RNA混合系统的新粗粒度模型，包括能够快速计算机模拟以确定动力学反应速率的马尔可夫链模型。这些混合模型还将在置换过程中参数化错配的产生和修复，使得使用DNA和RNA进行精确动力学控制的链置换反应的设计成为可能，从而允许复杂计算级联与生物信号的自然界面。将开发一种通用的DNA和RNA序列设计工具，重点关注四项任务：算法/效率改进，开发新模型以增强可表达为约束的行为，与现有工具集成，以及混合DNA的设计和实验演示：实现自稳定时钟的RNA置换系统，该奖项反映了NSF的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准。