Aromatic Amine DNA Structures--Mutagenic Relevance

芳香胺 DNA 结构--诱变相关性

• 批准号: 6522395
• 负责人: Suse Broyde
• 金额: $ 23.54万
• 依托单位: NEW YORK UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-01 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6522395
• 关键词: DNA damage; acetylaminofluorene; adduct; amines; chemical carcinogen; chemical carcinogenesis; computer simulation; frameshift mutation; gene deletion mutation; magnesium; molecular dynamics; mutagens; nucleic acid structure; nucleoside triphosphate; pyrenes; pyridine; quinoline

DESCRIPTION: (provided by applicant) The human population is routinely exposed to a large number of environmental chemicals: some of them may initiate cancer while others, only slightly different in structure, are harmless. One prominent route by which carcinogens exert their effects is to react with DNA in a way that leads to a mutation in a vital cellular target. Insight into the mechanism by which a carcinogen-damaged DNA produces mutations is needed in order to identify potentially hazardous substances. In this project, intensive computer modeling is used to explore this process. Our efforts here are targeted particularly to frameshift mutations, whose contribution to carcinogenesis has perhaps been underemphasized. In particular, we will attempt to relate chemical structure to mutagenic effectiveness within the framework of the slippage/misalignment theory. This theory has successfully explained the sequence dependence of many frameshift mutations. We will work with four aromatic amines, members of a chemical class that has demonstrated an exceptional ability to induce frameshifts. Our selection includes acetylaminofluorene (AAF), chosen because of the extensive data based concerning its mutagenicity, 2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine (PhIP) and 2-amino-3-methyl-imidazo(4,5-f)quinoline (IQ), carcinogens that are formed during the cooking of protein-rich foods, and 1-aminopyrene (AP), the transformation product of a common pollutant present in diesel engine exhaust, urban air particulates, and a number of other sources. We will follow the behavior of modified DNA primer-template complexes as they proceed through the steps of extension, blockage, and/or misalignment within the active sites of selected polymerases for which suitable crystal structures are available. Our methods include the use of the programs DUPLEX (for molecular mechanics with modified DNA) and AMBER for molecular dynamics simulations with DNA in solution or in a polymerase. DUPLEX permits an extensive search of conformation space without the use of assumptions concerning the final structure. The molecular dynamics studies include explicit solvent and salt, and provide animation, but are more restricted in their search. Molecular dynamics trajectories yield ensembles of structures that will be used to compute free energy differences between conformers in solution, and binding free energies of polymerase-primer-template complexes.

描述：（由申请人提供）通常暴露于人口 大量环境化学物质：其中一些可能引发癌症 而其他仅略有不同的结构则是无害的。一个突出 致癌物发挥作用的途径是以某种方式与DNA反应 这导致重要的细胞靶标的突变。洞悉机制 为了使致癌的DNA产生突变，以便 确定潜在的危险物质。在这个项目中，密集型计算机 建模用于探索此过程。 我们在这里的努力特别针对的是移码突变， 对致癌作用的贡献可能被低估了。尤其， 我们将尝试将化学结构与诱变的有效性联系起来 打滑/错位理论的框架。这个理论已成功 解释了许多移码突变的序列依赖性。我们将工作 与四个芳香胺一起，化学类的成员已经证明 诱导移架的出色能力。我们的选择包括 乙酰氨基氟烯（AAF），由于广泛的基于数据而选择 关于其诱变，2-氨基-1-甲基-6-苯基咪唑唑（4,5-B）吡啶 （pHIP）和2-氨基-3-甲基 - imidazo（4,5-F）喹啉（IQ），致癌物 在富含蛋白质的食物和1-氨基吡啶（AP）的过程中形成 柴油发动机排气中存在的常见污染物的转化产物， 城市空气颗粒物和许多其他来源。 我们将遵循修饰的DNA启动板复合物的行为 在内部进行扩展，阻塞和/或未对准的步骤 适当的晶体结构的选定聚合酶的活性位点 可用。我们的方法包括使用程序双工（用于 具有改性DNA的分子力学）和琥珀色的分子动力学 在溶液中或聚合酶中使用DNA的模拟。双工允许AN 不使用假设的大量搜索构象空间 关于最终结构。分子动力学研究包括明确的 溶剂和盐，并提供动画，但在他们的 搜索。分子动力学轨迹产生的结构集合 用于计算溶液中构象异构体之间的自由能差，并且 聚合酶 - 蛋白酶 - 塑料板复合物的结合自由能。