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）可以在诊断，治疗学和纳米级制造中进行有希望的应用自组装成纳米级结构和设备。链位移，其中入侵者单链位移与互补底物结合的现有链，是动态DNA纳米技术的关键过程。尽管事实证明，DNA链位移电路能够进行复杂的计算，但它们并不像生物系统（例如CRISPR）一样自然地接口。同时，RNA电路没有取得相同的成功水平。这项研究旨在建立对杂交DNA的更丰富的理解和精确控制：RNA位移，可能导致能够与生物系统进行互操作的分子回路中的全新水平。灵活，用户友好的序列设计工具将大大降低非专家实现的障碍。教育和外展活动将通过跨越主题界限来扩大多个学科的计算和跨培训学生的参与。研究人员将收集实验数据，以参数化DNA-RNA杂交系统的新粗粒模型，包括能够快速硅内模拟的马尔可夫链模型以确定动力学反应速率。这些混合模型还将在位移期间参数化不匹配的创建和修复，从而使使用DNA和RNA精确的动力学控制的链位移反应的设计可能，从而允许具有生物学信号的复杂计算级联反应。 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法定任务，并被认为是值得通过基金会的智力优点和更广泛影响的审查标准来评估的值得支持的。