Factors Stabilizing RNA Structures

稳定 RNA 结构的因素

• 批准号: 7941411
• 负责人: DAVID E. DRAPER
• 金额: $ 5.02万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7941411
• 关键词: Abbreviations; Accounting; Adopted; Affect; Antibiotics; Area; Attention; Calorimetry; Catalytic RNA; Cell physiology; Cells; Characteristics; Charge; Classification; Collaborations; Data; Development; Differential Scanning Calorimetry; Diffuse; Drug Delivery Systems; Electrostatics; Environment; Equilibrium; Evaluation; Free Energy; Future; Gene Expression; Goals; Grant; Health; Heating; Hydration status; Hydrogen; Ions; Measurement; Measures; Messenger RNA; Methods; Modeling; Molecular; Molecular Conformation; Monovalent Cations; Motivation; N-methylisatoic anhydride; Osmolar Concentration; Pharmaceutical Preparations; Process; Property; Protein Biosynthesis; Proteins; Quinolinic Acid; RNA; RNA Folding; RNA Stability; Radial; Reaction; Research Design; Ribosomal RNA; Roentgen Rays; Solutions; Solvents; Structure; Study Subject; Surface; Theoretical model; Thermodynamics; Titrations; Transfer RNA; Water; Work; design; enthalpy; experience; in vivo; methylisoamylnitrosamine; models and simulation; pressure; protein complex; research study; tool; trimethyloxamine; vapor

DESCRIPTION (provided by applicant): Folding of RNA molecules into specific tertiary structures is important for a large number of cellular processes relating to gene expression. For instance, protein synthesis requires transfer RNA and ribosomal RNAs to adopt functional structures, and processing of transfer and messenger RNAs depend on ribozymes or RNA-protein complexes which must also fold properly. The very high negative charge carried by RNA molecules limits their folding possibilities and causes the stabilities of folded RNAs to be very sensitive to the concentrations of Mg2+ and other ions present in solution. The long term goal of these studies is to provide a systematic and quantitative picture of ion and solvent interactions that stabilize RNA tertiary structures, and to relate the picture to the underlying electrostatic properties of RNA. A quantitative description of Mg2+ - RNA interactions that considers diffuse (hydrated) and chelated ions has been successful in accounting for the stabilities of some RNAs. To explore the limitations of this model, in future work close attention will be paid to RNAs with Mg2+ or monovalent ions in unusual environments, and the characteristics of the partially structured RNAs from which native structures fold will be studied. Other work will examine the effects of osmolytes, naturally occurring compounds accumulated by cells to high concentrations to maintain osmolarity, on RNA stability. Besides their relevance to the folding of RNAs in vivo, osmolytes may also be useful tools for characterizing the kinds of structures present in a RNA. Lastly, unusual effects of ions on the heat capacity of folded RNAs will be explored because of the potential implications for RNA hydration. Health relevance of the proposed work: Many cellular RNAs are directly involved in the synthesis of proteins, and other RNA structures regulate the levels of proteins in cells. Some of these RNAs are targets for natural antibiotics. Drugs which stabilize or alter specific critical RNA structures could have wide therapeutical applications. An understanding of the forces that stabilize RNA structures could aid in selection of drug targets and the design of new drugs.

描述（由申请人提供）：RNA分子折叠成特定的三级结构对于与基因表达相关的大量细胞过程非常重要。例如，蛋白质合成需要转移RNA和核糖体RNA来采用功能结构，而转移RNA和信使RNA的加工依赖于核酶或RNA-蛋白质复合物，它们也必须正确折叠。 RNA 分子携带的非常高的负电荷限制了它们的折叠可能性，并导致折叠 RNA 的稳定性对溶液中存在的 Mg2+ 和其他离子的浓度非常敏感。这些研究的长期目标是提供稳定 RNA 三级结构的离子和溶剂相互作用的系统和定量图像，并将该图像与 RNA 的潜在静电特性联系起来。考虑扩散（水合）离子和螯合离子的 Mg2+ - RNA 相互作用的定量描述已成功解释了某些 RNA 的稳定性。为了探索该模型的局限性，在未来的工作中，我们将密切关注异常环境中含有 Mg2+ 或单价离子的 RNA，并研究天然结构折叠的部分结构 RNA 的特征。其他工作将检查渗透剂（细胞为了维持渗透压而积累的高浓度天然化合物）对 RNA 稳定性的影响。除了与体内 RNA 折叠相关之外，渗透剂也可能是表征 RNA 中存在的结构类型的有用工具。最后，由于对 RNA 水合的潜在影响，离子对折叠 RNA 热容的不寻常影响将被探索。拟议工作的健康相关性：许多细胞 RNA 直接参与蛋白质的合成，其他 RNA 结构调节细胞中蛋白质的水平。其中一些 RNA 是天然抗生素的靶标。稳定或改变特定关键 RNA 结构的药物可能具有广泛的治疗应用。了解稳定 RNA 结构的力量有助于药物靶点的选择和新药的设计。