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Quantitative modeling of nucleic acid-protein interactions

核酸-蛋白质相互作用的定量模型

基本信息

批准号：
1719316
负责人：
Ralf Bundschuh
金额：
$ 33.58万
依托单位：
Ohio State University
依托单位国家：
美国
项目类别：
Standard Grant
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2020-12-31
项目状态：
已结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=1719316&HistoricalAwards=false
关键词：
Quantitative modeling nucleic acid protein

项目摘要

NONTECHNICAL SUMMARYThe Division of Materials Research and the Chemistry Division contribute funds to this award that supports theoretical research and education towards developing models for the interactions within nucleic acid and protein complexes. All living organisms use three main classes of biomolecules as their building blocks, nucleic acids (DNA and RNA), proteins, and lipids. Like Lego® pieces, these building blocks can be combined in myriads of different ways to give rise to all the complexities of living organisms. However, the rules by which these building blocks fit together (interact) are not well understood. The goal of this project is to develop mathematical models that describe the interactions of two of these building blocks, namely nucleic acids and proteins.Such mathematical models offer two advantages: i) They allow a better understanding of how living organisms work, ultimately improving our ability to correct instances when they do not work, i.e., diseases. ii) They allow these natural molecules to be assembled in new ways in engineered systems to provide completely new functionality. In developing these models, the research team works closely with collaborators performing experiments on real systems to test and improve the models. To be specific and to address both of the goals presented above, one subproject focuses on how the interactions between the nucleic acid RNA and proteins guide the formation of the outer shell of viruses in infected cells, while the other subproject focuses on dynamic human-engineered DNA nanostructures called DNA origami that one day could form the basis of nanorobots.In addition to the development of models that will improve understanding of diseases and enable novel engineering applications, the project will also train the next generation of researchers at the interface between life and physical sciences through their involvement in research, coursework, and seminars. This is important since Biology and Medicine on one side, and Physics, Mathematics, and Engineering on the other side traditionally use rather different languages and approaches; addressing the complex problems in Biology and Medicine today needs the more mathematical approaches that quantitative fields offer, and thus "bilingual" scientists who understand and speak the language of both are urgently needed.TECHNICAL SUMMARYThe Division of Materials Research and the Chemistry Division contribute funds to this award that supports theoretical research and education towards developing models for the interactions within nucleic acid and protein complexes. In a cell, proteins, RNA and DNA interact with each other in a highly controlled fashion. The ability to reproducibly form specific complexes from these molecules also enables their use in creating man-made nanoscale devices. In this project, quantitative models of the interactions within such complexes will be developed. Quantitative models are crucial for understanding biological functions of biomolecular complexes, for interpreting experiments on such biomolecular complexes, and for designing novel complexes. All activities are performed in close collaboration with experimentalists. The work in this project is divided into two main threads, one addressing interactions in natural biomolecular complexes and one addressing engineering man-made biomolecular complexes. The focus of the first subproject is on describing the interaction of double-stranded RNA binding proteins with RNA. Since these proteins are specific to double-stranded RNA, their binding to a given RNA molecule depends on the intramolecular interactions of the RNA molecule. One of the main goals of the project is the development of a model that can predict for arbitrary RNA molecules how strongly and at which locations a double-stranded RNA binding protein will bind. This will build upon the research team's previous experience and will result in a complete modeling framework for both of the common classes of RNA binding proteins. One important application of such a model is understanding the mechanism by which specific interactions between coat proteins and single-stranded RNA genome guide the assembly of the viral shell in certain RNA viruses. The other thread of the project focuses on developing models of dynamic DNA origami structures including those that incorporate functional mechanical elements, such as nucleosomes or RNA molecules. Such structures can be used to provide information on their immediate environment, perform functions such as drug delivery, and provide insight into the mechanical properties of biomolecules attached to them.In addition to the development of models that will improve understanding of diseases and enable novel engineering applications, the project will also train the next generation of researchers at the interface between life and physical sciences through their involvement in research, coursework, and seminars. This is important since Biology and Medicine on one side, and Physics, Mathematics, and Engineering on the other side traditionally use rather different languages and approaches; addressing the complex problems in Biology and Medicine today needs the more mathematical approaches that quantitative fields offer, and thus "bilingual" scientists who understand and speak the language of both are urgently needed.

材料研究部和化学部为该奖项提供资金，支持理论研究和教育，以开发核酸和蛋白质复合物内相互作用的模型。所有生物体都使用三种主要的生物分子作为其构建单元，即核酸（DNA和RNA）、蛋白质和脂质。就像乐高积木一样，这些积木可以以无数种不同的方式组合在一起，从而产生生物体的所有复杂性。然而，这些积木组合在一起（相互作用）的规则还没有得到很好的理解。该项目的目标是开发数学模型，描述其中两个构建模块，即核酸和蛋白质的相互作用。这种数学模型提供了两个优点：i）它们可以更好地理解生物体如何工作，最终提高我们在它们不起作用时纠正实例的能力，即，疾病ii）它们允许这些天然分子在工程系统中以新的方式组装，以提供全新的功能。在开发这些模型的过程中，研究团队与合作者密切合作，在真实的系统上进行实验，以测试和改进模型。具体来说，为了解决上述两个目标，一个子项目侧重于核酸RNA和蛋白质之间的相互作用如何指导感染细胞中病毒外壳的形成，而另一个子项目则侧重于动态的人-设计的DNA纳米结构称为DNA折纸，有一天可以形成纳米机器人的基础。除了模型的发展，将提高对该项目将通过参与研究、课程和研讨会，培养下一代生命科学和物理科学之间的研究人员。这一点很重要，因为一方面是生物学和医学，另一方面是物理学，数学和工程学，传统上使用相当不同的语言和方法;解决当今生物学和医学中的复杂问题需要定量领域提供的更多数学方法，因此，“双语”技术概要材料研究部和化学部为此提供了资金该奖项支持理论研究和教育，以开发核酸和蛋白质复合物内相互作用的模型。在细胞中，蛋白质、RNA和DNA以高度受控的方式相互作用。从这些分子中可重复地形成特定复合物的能力也使它们能够用于制造人造纳米级器件。在本项目中，将开发此类复合物内相互作用的定量模型。定量模型对于理解生物分子复合物的生物学功能、解释此类生物分子复合物的实验以及设计新型复合物至关重要。所有活动都是在与实验人员密切合作下进行的。该项目的工作分为两个主线，一个是解决天然生物分子复合物中的相互作用，另一个是解决工程人造生物分子复合物。第一个子项目的重点是描述双链RNA结合蛋白与RNA的相互作用。由于这些蛋白质对双链RNA具有特异性，因此它们与给定RNA分子的结合取决于RNA分子的分子内相互作用。该项目的主要目标之一是开发一种模型，可以预测任意RNA分子的双链RNA结合蛋白结合的强度和位置。这将建立在研究小组以前的经验基础上，并将为两种常见的RNA结合蛋白质类提供一个完整的建模框架。这种模型的一个重要应用是理解外壳蛋白和单链RNA基因组之间的特异性相互作用指导某些RNA病毒中病毒外壳组装的机制。该项目的另一个重点是开发动态DNA折纸结构的模型，包括那些包含功能性机械元件的模型，如核小体或RNA分子。这些结构可用于提供有关其直接环境的信息，执行药物递送等功能，并提供对附着于其上的生物分子的机械特性的洞察。除了开发将提高对疾病的理解并实现新的工程应用的模型外，该项目还将通过让下一代研究人员参与研究、课程和研讨会，在生命科学和物理科学之间的接口方面对他们进行培训。这一点很重要，因为一方面生物学和医学，另一方面物理学，数学和工程学传统上使用相当不同的语言和方法;解决当今生物学和医学中的复杂问题需要定量领域提供的更多数学方法，因此迫切需要能够理解和使用两者语言的“双语”科学家。