NUPACK: New Capabilities for Nucleic Acid Analysis and Design

在化学系化学理论、模型和计算方法计划的支持下，加州理工学院(Caltech)的奈尔斯·A·皮尔斯教授将为核酸分析和设计开发新的算法。核酸(DNA和RNA)通过在复杂的生物回路中相互作用来协调生命，以生长、调节和修复有机体。在未来几十年里，在分子编程、核酸纳米技术和合成生物学等新兴领域进行DNA和RNA工程将产生变革性的可编程分子和细胞技术，以应对从环境监测和生物圈工程到诊断和治疗以及从可再生能源到可持续制造的各种科学和社会挑战。为了支持这些工程工作，加州理工大学的皮尔斯实验室致力于开发NUPACK(核酸包)，这是一个不断增长的分析和设计核酸结构、设备和系统的软件套件。在这里，他们将通过追求三个主要目标来扩大NUPACK的能力。首先，他们的目标是开发能够模拟具有运动部件的功能核酸系统的算法。其次，他们将开发分析和设计算法，使含有混合材料(例如，DNA和RNA，或DNA和合成核酸类似物，如LNA)的系统能够处理，这些材料对现代应用至关重要，无论是在活体中，在实验室工作台上，还是在现场。第三，他们将努力推广NUPACK云网络应用程序，使用户能够有效地利用这些独特的计算工具进行研究和教育。NUPACK是一个不断发展的软件套件，用于分析和设计核酸结构、设备和系统，满足分子编程、核酸纳米技术、合成生物学和整个生命科学等新兴学科的研究人员的需求。NUPACK算法在处理包含任意数量相互作用链物种的复杂和试管组合方面是独一无二的，为捕获浓度效应提供了关键工具，这些效应对于分析和设计分子间相互作用至关重要，分子间相互作用是这些领域的标志。在这里，加州理工大学的皮尔斯实验室建议通过追求三个主要目标来显著扩展NUPACK的能力。首先，为了能够模拟具有运动部件的功能核酸系统，他们将开发自动化的动力学粗粒化算法，以便能够对复杂的和试管系综进行动力学分析。其次，为了能够在体外、原位和体内对现代应用至关重要的混合材料系统(例如DNA/RNA或LNA/DNA)进行工程设计，他们将开发混合材料模型和算法，用于分析和设计复杂的和试管组合。第三，他们将推广NUPACK云Web应用程序以涵盖这些新功能，使研究人员和学生能够在可扩展的NUPACK混合云中通过并行执行高效地利用这些独特的工具。这些新的分析和设计能力预计将产生广泛的科学影响，有助于新的分子和细胞技术的发展，这些技术最终将具有从环境监测和生物圈工程到核酸疗法开发的广泛应用。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

With support from the Chemical Theory, Models and Computational Methods program in the Division of Chemistry, Professor Niles A. Pierce of the California Institute of Technology (Caltech) will develop new algorithms for nucleic acid analysis and design. Nucleic acids (DNA and RNA) orchestrate life by interacting within complex biological circuits to grow, regulate, and repair organisms. Over the coming decades, engineering of DNA and RNA within the emerging fields of molecular programming, nucleic acid nanotechnology, and synthetic biology are poised to generate transformative programmable molecular and cellular technologies addressing diverse challenges to science and society ranging from environmental monitoring and biosphere engineering to diagnosis and treatment, and from renewable energy to sustainable manufacturing. To support these engineering efforts, the Pierce Lab at Caltech is engaged in a multi-decade effort to develop NUPACK (Nucleic Acid Package), a growing software suite for analyzing and designing nucleic acid structures, devices, and systems. Here, they will expand NUPACK’s capabilities by pursuing three major goals. First, they aim to develop algorithms to enable simulation of functional nucleic acid systems with moving parts. Second, they will develop analysis and design algorithms that enable treatment of systems that contain mixed materials (e.g., both DNA and RNA, or both DNA and a synthetic nucleic acid analog such as LNA) that are critical to modern applications whether in living organisms, on the laboratory bench, or in the field. Third, they will endeavor to generalize the NUPACK cloud web app to enable users to efficiently leverage these unique computational tools for both research and education. NUPACK is a growing software suite for the analysis and design of nucleic acid structures, devices, and systems serving the needs of researchers in the emerging disciplines of molecular programming, nucleic acid nanotechnology, synthetic biology, and across the life sciences. NUPACK algorithms are unique in treating complex and test tube ensembles containing arbitrary numbers of interacting strand species, providing crucial tools for capturing concentration effects essential to analyzing and designing the intermolecular interactions that are a hallmark of these fields. Here, the Pierce Lab at Caltech proposes to significantly expand NUPACK's capabilities by pursuing three major goals. First, to enable simulation of functional nucleic acid systems with moving parts, they will develop automated kinetic coarse-graining algorithms to enable kinetic analysis of complex and test tube ensembles. Second, to enable engineering of mixed-material systems (e.g., DNA/RNA or LNA/DNA) that are critical for modern applications in vitro, in situ, and in vivo, they will develop mixed-material models and algorithms for the analysis and design of complex and test tube ensembles. Third, they will generalize the NUPACK cloud web app to encompass these new capabilities, enabling researchers and students to efficiently leverage these unique tools with parallel execution in the scalable NUPACK hybrid cloud. These new analysis and design capabilities are expected to have broad scientific impact, contributing to the development of new molecular and cellular technologies that will ultimately have applications ranging from environmental monitoring and biosphere engineering to the development of nucleic acid therapeutics.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.