AF: Medium: Collaborative Research: Top-down algorithmic design of structured nucleic acid assemblies

在过去的十年里，使用自组装核酸“打印”复杂的纳米级结构和图案的能力有了显著的增长。这些结构可以用作模板来合成1-100纳米尺度的无机材料，或者直接用于诸如基于DNA的存储器存储、治疗递送、单分子结构确定和纳米级激子材料等应用中。虽然各种计算策略可用于从底层DNA或RNA序列和拓扑结构手动正向设计这些复杂的3D结构，但仅从靶几何形状自主生成线性核酸序列的逆问题仍然是未解决的计算挑战。在这个项目中，全自动的，自上而下的计算机辅助设计（CAD）算法进行了探索，以产生拓扑序列设计的广泛类别的编程DNA和RNA组件在一个自主的方式，单独使用目标的几何形状。这些组件可以通过体外或体内自组装来“打印”，以使用合成或转录的核酸形成靶纳米级几何形状。该方法将提供一个广泛使用的，高级编程语言，实现基于核酸的任意1D/2D/3D纳米结构材料的基于序列的编程，在基础科学和纳米技术中具有不同的应用。所提出的计算算法将作为开源软件在网上免费发布，并集成到各种软件包中，以广泛地实现最高-DNA和RNA组装的向下设计。这些算法和软件将为更广泛的科学和工业界提供易于使用的高水平设计策略，这将加速群体广泛参与核酸纳米技术在生物分子和材料科学技术中的各种应用。这些工具将为高中生和大学生提供机会，获得核酸纳米结构设计的实践经验。亚利桑那州立大学和麻省理工学院的课程开发将使用这种序列设计软件，让本科生和研究生参与其在计算机科学和纳米技术研究中的基本问题的使用和应用。将探索使用DNA和RNA设计纳米结构材料的基础方面。将研究使用DNA和RNA绘制各种基于CAD的几何图元的数学方法，包括2D和3D中的线框网格，可能包含任意曲率的单层表面以及3D固体对象。网格算法将用于离散化1D、2D和3D中的几何对象，拓扑路由和序列设计将用于在CAD对象内定位核酸链。连续和不连续的单链核酸将使用反平行和平行交叉构型通过双链体路由，以利用不同的程序化自组装模式。序列设计和路由将通过实验验证，以探索在3D空间中获得最佳折叠，自组装和特定碱基对定位的原理。此外，还将探索RNA纳米结构的自组装，利用来自单个长的连续支架链的无钉设计。实验和计算之间的密切互动将有助于提炼出基本而实用的方法来编程结构化核酸组装。

The past decade has witnessed dramatic growth in ability to "print" complex nanometer-scale structures and patterns using self-assembling nucleic acids. These structures can be used as templates to synthesize inorganic materials on the 1-100 nanometer-scale, or employed directly in applications such as DNA-based memory storage, therapeutic delivery, single-molecule structure-determination, and nanoscale excitonic materials. While various computational strategies are available to forward design these complex 3D structures manually from underlying DNA or RNA sequence and topology, the inverse problem of autonomously generating linear nucleic acid sequences from target geometry alone remains an unsolved computational challenge. In this project, fully automatic, top-down computer-aided design (CAD) algorithms are explored to generate topological sequence designs for broad classes of programmed DNA and RNA assemblies in an autonomous manner using target geometry alone. These assemblies can be "printed" via self-assembly in vitro or in vivo to form target nanoscale geometries using either synthetic or transcribed nucleic acids. The approach will offer a broadly accessible, high-level programming language to realize sequence-based programming of arbitrary 1D/2D/3D nanoscale structured materials based on nucleic acids with diverse applications in basic science and nanotechnology.The proposed computational algorithms will be distributed freely online as open source software as well as integrated into a variety of software packages to broadly enable the top-down design of DNA and RNA assemblies. These algorithms and software will provide the broader scientific and industrial communities with easy-to-use, high-level design strategies that will accelerate the broad participation of groups in the use of nucleic acid nanotechnology for diverse applications in biomolecular and materials science and technology. The tools will open up opportunities for high school students and undergraduates to gain hands-on experience in nucleic acid nanostructure design. Curriculum developments at ASU and MIT will employ the use of this sequence design software for participation by undergraduate and graduate students in its use and application to basic questions in computer science and nanotechnology research.Foundational aspects of the design of nanoscale structured materials using DNA and RNA will be explored. Algorithmic approaches to rendering diverse CAD-based geometric primitives using DNA and RNA will be investigated, including wireframe lattices in 2D and 3D, single-layer surfaces that may contain arbitrary curvatures, as well as 3D solid objects. Meshing algorithms will be used to discretize geometric objects in 1D, 2D, and 3D, and topological routing and sequence design will be applied to position nucleic acid strands within CAD objects. Continuous and discontinuous single stranded nucleic acids will be routed through duplexes using anti-parallel and parallel crossover configurations to exploit distinct modes of programmed self-assembly. Sequence design and routing will be validated experimentally to explore principles for obtaining optimal folding, self-assembly, and positioning of specific base pairs in 3D space. Self-assembly of nanostructures from RNA will additionally be explored, utilizing staple-free designs from single long continuous scaffold strands. Close interaction between experiment and computation will help to distill fundamental yet practical approaches to programming structured nucleic acid assemblies.