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Structual Studies for Nucleic Acids Conformation as Genetic Signal and Regulational Signal

作为遗传信号和调节信号的核酸构象的结构研究

基本信息

批准号：
61460224
负责人：
FUJII SATOSHI
金额：
$ 2.75万
依托单位：
FACULTY OF PHARMACEUTICAL SCIENCES, OSAKA UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (B)
财政年份：
1986
资助国家：
日本
起止时间：
1986 至 1987
项目状态：
已结题

项目摘要

Nucleic acid molecules don't exist as a rigid and uniform structure. DNA molecules with a certain base sequence has a special structure which may act genetic signal. We determined some interesting structures by X-ray determination. NMR measurement and molecular dynamic simulation. 1. DNA molecule with adenine tract which causes a bending structure, d(CGCAAAAAAGCG):d(CGCTTTTTTGCG) was crystallized and its crystal structure was determined. No bending conformation was observed in crystalline state. 2. 500Mz proton NMR measurement of the above DNA molecule was carried at room temperature. Nuclear Overhauser effects were analysed and the molecular dynamic simulations with proton-proton distance restraint were calculations. The obtained molecular structure has two strictly bending sites. Both bending sites exist between adenine tract region and non-adenine tract region. No bending was observed in adenine tract region. These results support the junkction model for bending mechanism of adenine tract. 3. An antitumor agent, cis platinum (cis-Pt) adopts at N7 positions of two adjacenting guanine bases. By 500Mz proton NMR measurement of cis-Pt complex with d(CGAACGGCGCG):d(CGCGCCTTGCG), drug attachment to DNA double helices destabilizes but causes no breakdown of hydrogen bond formation in base pairing. by the model study, the kink conformation at drug attached site with open form at minor groove is proposed. 4. The suitable conformations of DNA molecule with I-A base pairing, were seeked by molecular mechanics and dynamic simulation calculations. Two possible conformations which have a similar conformational energy, can be changable. These are consist with NMR studies of d(CGCIAATTAGCG).

核酸分子并不以刚性且均匀的结构存在。具有一定碱基序列的DNA分子具有特殊的结构，可以作用于遗传信号。我们通过 X 射线测定确定了一些有趣的结构。核磁共振测量和分子动力学模拟。 1.使具有导致弯曲结构的腺嘌呤束的DNA分子d(CGCAAAAAAGCG):d(CGCTTTTTTGCG)结晶并测定其晶体结构。在结晶状态下没有观察到弯曲构象。 2.在室温下对上述DNA分子进行500Mz质子NMR测量。分析了核奥沃豪塞效应，并计算了质子-质子距离约束下的分子动力学模拟。获得的分子结构具有两个严格弯曲的位点。两个弯曲位点都存在于腺嘌呤束区域和非腺嘌呤束区域之间。在腺嘌呤束区域没有观察到弯曲。这些结果支持腺嘌呤束弯曲机制的连接模型。 3.抗肿瘤剂顺式铂(cis-Pt)采用在两个相邻鸟嘌呤碱基的N7位置。通过 500Mz 质子 NMR 测量顺式 Pt 与 d(CGAACGGCGCG):d(CGCGCCTTGCG) 的复合物，药物附着在 DNA 双螺旋上会破坏稳定性，但不会导致碱基配对中氢键形成的破坏。通过模型研究，提出了小沟开放形式的药物附着位点的扭结构象。 4.通过分子力学和动态模拟计算，寻找具有I-A碱基配对的DNA分子的合适构象。具有相似构象能的两种可能的构象是可以改变的。这些与 d(CGCIAATTAGCG) 的 NMR 研究一致。