Factors Stabilizing RNA Structures

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有关的大量细胞过程是重要的。例如，蛋白质合成需要转移RNA和核糖体RNA采用功能结构，转移和信使RNA的处理依赖于核酶或RNA-蛋白质复合体，它们也必须适当折叠。RNA分子携带的非常高的负电荷限制了它们的折叠可能性，并使折叠的RNA的稳定性对溶液中存在的镁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的潜在静电性质联系起来。考虑扩散(水合)和螯合离子的镁-RNA相互作用的定量描述已经成功地解释了一些RNA的稳定性。为了探索该模型的局限性，在未来的工作中，将密切关注在特殊环境中含有镁离子或单价离子的RNA，并将研究从中折叠自然结构的部分结构RNA的特征。其他工作将检查渗透素类对RNA稳定性的影响。渗透素类是细胞为维持渗透压而积累到较高浓度的天然化合物。除了它们与体内RNA折叠的相关性外，渗透分子也可能是表征RNA中存在的结构类型的有用工具。最后，由于离子对RNA水合作用的潜在影响，我们将探讨离子对折叠RNA热容的不寻常影响。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，而其他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结构的作用力有助于药物靶点的选择和新药的设计。

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.