HIGHER ORDER NUCLEIC ACID SOLUTION STRUCTURES

高阶核酸溶液结构

• 批准号: 2177463
• 负责人: DINSHAW J PATEL
• 金额: $ 24.02万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 1984
• 资助国家: 美国
• 起止时间: 1984-12-01 至 1999-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2177463
• 关键词: DNA; RNA; cations; chemical binding; conformation; guanine; hydrogen bond; intermolecular interaction; molecular dynamics; molecular polarity; nuclear magnetic resonance spectroscopy; nucleic acid sequence; nucleic acid structure; peptides; sodium; stereochemistry; structural biology; synthetic nucleic acid; telomere; triple helix; water solution

This competing renewal application applies a combined NMR-molecular dynamics approach to structural issues related to the formation, folding topology, stability and interactions of nucleic acid triplexes and G- quadruplexes in aqueous solution. The triplex research is directed towards a molecular understanding of oligonucleotide directed recognition of duplex DNA and addresses approaches to overcome the acidic pH requirement for formation of pyr.purpyr triplexes and the non-isomorphous positions of triples in pur.purpyr triplexes. Structural studies will also address the conformation at triplex-triplex junctions associated with alternate strand recognition and potential discontinuities at triplex-duplex junctions. The helical structures of hybrid triplexes involving DNA, RNA and PNA (peptide nucleic acid) strands will be elucidated as will triple pairing alignments and structures of triple stranded intermediates in genetic recombination. The structural studies on G-quadruplexes formed by guanine rich telomeric repeats will be extended to the single repeat G-rich Bombyx mori d(T2AG2T) and the two repeat G-rich Plasmodium d(AG3T3AG3) and Saccharomyces cerevisiae d[G3(TG)2,3TG3] telomeric sequences to elucidate the folding topologies and their potential monovalent and divalent cation dependent conformational transitions. The solution structures of the four repeat G-rich human d[AG3(T2AG3)3] and Tetrahymena d(T2G4)4 telomeric sequences determined previously in our laboratory will be monitored as a function of deletions, additions and substitutions within critical linker segments. The integrity of junctional base pairs at G-quadruplex-duplex junctions will be studied and modulations of the structure followed on insertion of junctional bulge residues. Related studies will investigate the alignment of a pair of helices projecting from a G-tetrad face and variations in their relative positioning and cavity formation following appropriate junctional bulge insertions. We shall attempt to generate and characterize G-quadruplexes from RNA and PNA sequences towards an improved understanding of the contributions of backbone conformation and charge to folding topology and stability. These structural studies will provide a molecular foundation for efforts directed towards an improved understanding of oligonucleotide directed sequence specific recognition of duplex DNA through triplex formation, as well as define the range of folding topologies adopted by guanine rich telomeric G-quadruplexes that have been implicated in chromosomal organization and association during the cell cycle.

此竞争续订应用程序应用于NMR分子的组合 与形成相关的结构性问题的动态方法，折叠 拓扑，稳定性和核酸三重和G-的相互作用 水溶液中的四链体。三元研究针对 对寡核苷酸的分子理解的定向识别 双链DNA并解决了克服酸性pH要求的方法 为了形成Pyr.purpyr三环和非异顺位 纯度三元。结构研究也将解决 与交替链相关的三重三重连接处的构象 三链连接连接处的识别和潜在不连续性。 涉及DNA，RNA和PNA的混合三环的螺旋结构 （肽核酸）将阐明链，而三重配对 遗传中三链中间体的比对和结构 重组。鸟嘌呤形成的关于G四链体的结构研究 丰富的端粒重复量将扩展到单个重复G-RICH BOMBYX mori d（T2AG2T）和两个重复富含G的疟原虫D（AG3T3AG3）和 酿酒酵母D [G3（TG）2,3TG3]端粒序列以阐明 折叠拓扑及其潜在的一价和二价阳离子 依赖构象转变。四个解决方案结构 重复富含G的人D [AG3（T2AG3）3]和四膜hymena D（T2G4）4端粒 先前在我们的实验室中确定的序列将被监测为 关键链接器中删除，添加和替换的功能 细分市场。连接基底对的完整性在g Quadruplex-uplex 将研究结构的结构调制 连接凸出残基的插入。相关研究将调查 从G-Tetrad脸部投射的一对螺旋螺旋的对齐和 其相对定位和空腔形成的变化 适当的连接凸起插入。我们将尝试产生和 从RNA和PNA序列到改进的G-四链体的表征 理解骨干构象的贡献和对 折叠拓扑和稳定性。这些结构研究将提供 分子基础，用于方向改进的努力 了解寡核苷酸的定向序列特定识别 双链DNA通过三元形成，并定义 鸟嘌呤富含端粒G-四链体采用的折叠拓扑结构 与染色体组织和关联有关 细胞周期。