Collaborative Research:Recognition of RNA Structure Motifs Using Small Molecules

有了这一奖项，莱斯大学的Edward Nikonowicz博士和M.D.Anderson癌症中心的张树兴博士将识别和表征选择性地与独特的RNA结构基序结合的小分子。该奖项是通过化学部的生命过程化学(CLP)计划、分子和细胞生物科学部的遗传机制群以及NSF的计算和数据科学与工程(CDS&amp；E)计划颁发的。核糖核酸(RNA)在生物学中的核心作用早已被认识到，但大量不能翻译成蛋白质的“非编码”RNA分子，以及这些RNA的不同功能，直到最近十年才被曝光。该项目的目标是确定一系列化合物，这些化合物与非编码RNA分子中发现的特殊结构的小分子具有高选择性和亲和力。这些化合物可以作为生物技术和生化研究的新工具，以及在医学上的应用。除了通过研究生的研究支持培训外，该项目还将支持高中生和本科生使用现代化学、生物物理和计算工具来解决RNA和化学生物学中的基本问题的培训。学生们在当地的科学会议上展示他们的工作，让他们接触到科学界，并有机会将他们的结果传达给具有科学素养的广泛受众。非编码RNA(NC-RNA)，包括rRNA、核糖开关和前microRNA，通常具有包括对分子结构和功能重要的各种非规范特征的体系结构。因此，详细的结构为解释功能和机制研究提供了重要的背景。与特定RNA结构基序结合的小分子可以成为探测RNA构象和折叠的有力工具，并有助于体外和体内特定RNA活性的研究。核磁共振波谱将被用来定义一组频繁出现的非正则RNA元素访问的构象空间的宽度。将开发一种计算工作流程，将核磁共振定义的结构信息和虚拟化学库的电子筛选结合在一起，以识别选择性地与特定非正则元素结合的化合物。这些小分子与RNA的相互作用将用生物物理和高分辨结构方法来表征，包括核磁共振光谱和X射线结晶学。

With this award, Drs. Edward Nikonowicz (Rice University) and Shuxing Zhang (M. D. Anderson Cancer Center) will identify and characterize small molecules that selectively bind to unique RNA structure motifs. This award is being made through the Chemistry of Life Processes (CLP) Program of the Chemistry Division, the Genetic Mechanisms Cluster of the Division of Molecular and Cellular Biosciences, and the Computational and Data-Enabled Science and Engineering (CDS&E) Program at NSF. The central role of ribonucleic acids (RNAs) in biology has long been recognized, but the large number of "non-coding" RNA molecules, which are not translated into a protein, and the diverse functions of these RNAs have only come to light in the last decade. The goal of this project is to identify a collection of chemical compounds that bind with high selectivity and affinity to small elements of unusual structure found in non-coding RNA molecules. These compounds could be used as new tools for biotechnological and biochemical research and for applications in medicine. In addition to supporting the training through research of graduate students, this project will support training of high-school and undergraduate students in the use of modern chemical, biophysical, and computational tools to address fundamental problems in RNA and chemical biology. Students present their work at local scientific meetings, giving them exposure to the scientific community and the opportunity to communicate their results to a scientifically literate, yet broad audience.Non-coding RNAs (nc-RNA), including rRNAs, riboswitches, and pre-microRNAs, often have an architecture that includes a variety of non-canonical features important for the molecules' structures and function. Therefore, the detailed structure provides an important backdrop to interpret functional and mechanistic studies. Small molecules that bind to specific RNA structure motifs can become powerful tools for probing RNA conformation and folding and to facilitate the study of specific RNA activities in vitro and in vivo. NMR spectroscopy will be used to define the breadth of conformational space accessed by a set of frequently occurring non-canonical RNA elements. A computational workflow that integrates the NMR-defined structure information and the in silico screening of virtual chemical libraries will be developed to identify chemical compounds that selectively bind to specific non-canonical elements. The interactions of these small molecules with RNAs will be characterized using biophysical and high-resolution structure methods including NMR spectroscopy and X-ray crystallography.