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相关的大量细胞过程是重要的。例如，蛋白质合成需要转运RNA和核糖体RNA采用功能结构，而转运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分子携带的极高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Mg 2+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的图片，并将图片与RNA的潜在静电性质相关联。考虑扩散（水合）和螯合离子的Mg 2 + - 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。为了探索这种模型的局限性，在未来的工作中，将密切关注RNA与Mg 2+或单价离子在不寻常的环境中，和部分结构化的RNA的特性，天然结构的折叠将进行研究。其他的工作将检查渗透压调节剂的影响，渗透压调节剂是细胞积累到高浓度以维持渗透压的天然化合物，对RNA稳定性的影响。除了与RNA在体内的折叠相关外，渗透剂也可能是表征RNA中存在的结构种类的有用工具。最后，离子对折叠RNA的热容的不寻常的影响将被探索，因为RNA水合的潜在影响。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，其他RNA结构调节细胞中蛋白质的水平。其中一些RNA是天然抗生素的靶点。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结构的力量可以帮助选择药物靶点和设计新药。

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.