RNA Dynamics by Solution and Solid State Deuterium NMR

通过溶液和固态氘 NMR 进行 RNA 动力学分析

• 批准号: 1613678
• 负责人: Gabriele Varani
• 金额: $ 69.04万
• 依托单位: University of Washington
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-15 至 2020-06-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1613678&HistoricalAwards=false
• 关键词: RNA; Dynamics; Solution; Solid; State

Title: Functional dynamics in microRNA precursors by NMR Ribonucleic acid (RNA) performs many essential functions in all living organisms. MicroRNAs are an important class of RNAs that regulate the vast majority of the human genome, however the molecular mechanism by which these microRNAs are produced from precursor species is unclear. The dynamic structure of the precursor species have implications on microRNA processing. The project investigates how intrinsic motional properties of the RNA and RNA-binding proteins regulate the biological pathways associated with RNA regulation of gene expression, as a paradigm to understanding the molecular logic of regulation. This research will be executed in a highly interdisciplinary manner, which will allow training of postdoctoral fellows and graduate students to interdisciplinary research at the interface of physics, chemistry and molecular biology. The project will involve under-represented minority students who will be included in the research activities. Material from the project will also be used in teaching at the graduate level and in specialized advanced undergraduate courses. The overarching goal of this project is to study the relationship between RNA motion and its biological function. The specific objective of the research is to understand how microRNAs are produced in a manner that is regulated in different cellular states. This project will investigate how RNA dynamics, intrinsic to RNA, is altered upon substrate binding and its effects on the efficiency of processing of microRNA precursors. Primarily solution and solid-state NMR will be used and advanced spectroscopic techniques will be developed. Experimental studies will be integrated into state-of-the-art computational modeling for atomistic level interpretation. Biochemical and cell-based experiments will also be performed to test the biological functional relevance of the project's discoveries. Spectroscopic tools developed within this project to study functional dynamics in RNA will be broadly applicable to other nucleic acid systems.This project is supported by Molecular and Cellular Biosciences Division in the Directorate for Biological Sciences.

核磁共振核糖核酸(RNA)在microRNA前体中的功能动力学在所有活着的生物体中都具有许多基本功能。MicroRNAs是一类重要的RNAs，调节人类基因组的绝大多数，然而这些microRNAs是由前体物种产生的分子机制尚不清楚。前体物种的动态结构对microRNA的加工有影响。该项目研究RNA和RNA结合蛋白的内在运动特性如何调控与RNA调控基因表达相关的生物途径，以此作为理解调控的分子逻辑的范例。这项研究将以高度跨学科的方式进行，这将使博士后研究员和研究生能够在物理、化学和分子生物学的界面上进行跨学科研究。该项目将涉及代表人数不足的少数族裔学生，他们将被纳入研究活动。该项目的材料还将用于研究生水平的教学和专业高级本科课程。这个项目的首要目标是研究RNA运动与其生物学功能之间的关系。这项研究的具体目标是了解microRNAs是如何以一种在不同细胞状态下受到调节的方式产生的。本项目将研究RNA固有的RNA动力学在底物结合时是如何改变的，以及它对microRNA前体加工效率的影响。将主要使用溶液和固态核磁共振，并将开发先进的光谱技术。实验研究将被整合到最先进的计算模型中，用于原子水平的解释。还将进行生化和基于细胞的实验，以测试该项目发现的生物功能相关性。在这个项目中开发的研究RNA功能动力学的光谱工具将广泛适用于其他核酸系统。该项目得到了生物科学局分子和细胞生物科学司的支持。

项目成果

Molecular basis for the increased affinity of an RNA recognition motif with re-engineered specificity: A molecular dynamics and enhanced sampling simulations study

• DOI: 10.1371/journal.pcbi.1006642
• 发表时间: 2018-12-01
• 期刊: PLOS COMPUTATIONAL BIOLOGY
• 影响因子: 4.3
• 作者: Bochicchio, Anna;Krepl, Miroslav;Carloni, Paolo
• 通讯作者: Carloni, Paolo

Structure of a low-population binding intermediate in protein-RNA recognition

• DOI: 10.1073/pnas.1521349113
• 发表时间: 2016-06-28
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Borkar, Aditi N.;Bardaro, Michael F., Jr.;Vendruscolo, Michele
• 通讯作者: Vendruscolo, Michele