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.
