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Sequence Specific Targeting of RNA Using Complementary Strands: Energetics, Kinetics and Hydration

使用互补链的 RNA 序列特异性靶向：能量学、动力学和水合

基本信息

批准号：
1912587
负责人：
Luis Marky
金额：
$ 90万
依托单位：
University of Nebraska Medical Center
依托单位国家：
美国
项目类别：
Standard Grant
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=1912587&HistoricalAwards=false
关键词：
Sequence Specific Targeting RNA Using

项目摘要

Ribonucleic acid (RNA) is known to play a central role in a wide variety of cellular processes. To exert their function, RNA molecules must fold into a specific three-dimensional structure. In this project, the PI and his students will study the folding energetics and hydration properties of complex RNA structures and will determine the thermodynamics and kinetics governing their association with complementary strands. This would help improve our current understanding of the physical factors that determine their stability, melting behavior and structure, which are basic to the rational design of targeting strategies and computational models. Furthermore, the data obtained in this project will be compiled on a free-to-access website and applied to molecular modeling of RNA structures to show that detailed thermodynamics is needed to bring RNA modeling to the same accuracy as DNA modeling. This project will have societal impacts in the mentoring of young scientists, including high school, undergraduate and graduate students, and postdoctoral fellows. The project will develop biophysical methods and will train students in a wide variety of biophysical techniques, exposing them to a diverse range of topics in the physical sciences. The PI incorporates the research findings into curricular enrichment and seminar presentations. The student presentations of their work at scientific conferences allow them to integrate within the scientific community. Furthermore, the PI recruits students from diverse groups to participate in the Summer undergraduate research program at his institution, co-organizes a educational workshop every other year in "Structural Biology and Molecular Biophysics" in the Midwest; and attends the annual SACNAS meeting to increase the participation of young scientists from diverse groups into biophysics. The PI's laboratory will obtain nearest-neighbor data on intramolecular RNA secondary structures and use this data to improve structural modeling and targeting of RNA. In particular, the project aims to determine the unfolding thermodynamics of RNA stem-loop motifs, pseudoknots, stem-loop motifs with bulges, three and four way junctions, and biologically relevant RNA riboswitches, such as preQ1, SAM-II, and adenine riboswitch, as a function of sequence, loop length and solution conditions. The thermodynamic results will be correlated with hydration and SAXS structural data. The PI will also study the thermodynamic contributions and kinetic rates governing the reaction of intramolecular RNA structures with their partially complementary strands (SS) via duplex formation and the molecular forces governing the formation of SS-polycation complexes and to use SS-polycation complexes for targeting RNA structures.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.

众所周知，核糖核酸（RNA）在多种细胞过程中起着核心作用。为了发挥其功能，RNA分子必须折叠成特定的三维结构。在这个项目中，PI和他的学生将研究复杂RNA结构的折叠能量学和水合性质，并将确定控制它们与互补链结合的热力学和动力学。这将有助于提高我们目前对决定其稳定性、熔化行为和结构的物理因素的理解，这是合理设计目标策略和计算模型的基础。此外，本项目获得的数据将被汇编在一个免费访问的网站上，并应用于RNA结构的分子建模，以表明需要详细的热力学才能使RNA建模达到与DNA建模相同的精度。该项目将对青年科学家（包括高中生、本科生、研究生和博士后）的指导产生社会影响。该项目将发展生物物理方法，并培养学生广泛的生物物理技术，使他们接触到物理科学中各种各样的主题。PI将研究成果纳入课程充实和研讨会报告中。学生在科学会议上展示他们的工作，使他们能够融入科学界。此外，PI招收不同群体的学生参加他所在机构的夏季本科生研究项目，每隔一年在中西部共同组织一次“结构生物学和分子生物物理学”的教育研讨会；并参加一年一度的SACNAS会议，以增加来自不同群体的年轻科学家对生物物理学的参与。PI的实验室将获得分子内RNA二级结构的最近邻数据，并利用这些数据改进RNA的结构建模和靶向。特别是，该项目旨在确定RNA茎环基序、假结、带凸起的茎环基序、三路和四路连接以及生物学相关的RNA核糖开关（如preQ1、SAM-II和腺嘌呤核糖开关）的展开热力学，作为序列、环长度和溶液条件的函数。热力学结果将与水化和SAXS结构数据相关联。PI还将研究分子内RNA结构与其部分互补链（SS）通过双相形成反应的热力学贡献和动力学速率，以及控制SS-多阳离子复合物形成的分子力，并使用SS-多阳离子复合物靶向RNA结构。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。