Aromatic Amine DNA Structures--Mutagenic Relevance

芳香胺 DNA 结构--诱变相关性

• 批准号: 6655577
• 负责人: Suse Broyde
• 金额: $ 28.08万
• 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/6655577
• 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）人群经常接触 大量环境化学物质：其中一些可能引发癌症 而另一些结构仅略有不同，是无害的。一位杰出的 致癌物发挥作用的途径是与DNA发生反应 导致重要细胞靶标发生突变。深入了解机制 需要由致癌物质损伤的 DNA 产生突变，才能 识别潜在危险物质。在这个项目中，密集的计算机 建模用于探索这个过程。 我们在这里的努力特别针对移码突变，其 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效果联系起来 滑移/不对中理论的框架。这个理论已经成功 解释了许多移码突变的序列依赖性。我们将工作 含有四种芳香胺，属于化学类别的成员，已证明 诱导移码的特殊能力。我们的选择包括 乙酰氨基芴 (AAF)，因其基于大量数据而被选择 关于其致突变性，2-氨基-1-甲基-6-苯基咪唑并(4,5-b)吡啶 (PhIP) 和 2-氨基-3-甲基-咪唑(4,5-f)喹啉 (IQ) 是致癌物质 在烹饪富含蛋白质的食物过程中形成的 1-氨基芘 (AP) 柴油发动机废气中常见污染物的转化产物， 城市空气颗粒物和许多其他来源。 我们将跟踪修饰的 DNA 引物-模板复合物的行为，因为它们 继续执行延伸、阻塞和/或错位的步骤 具有合适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 DUPLEX 程序（用于 DNA 修饰的分子力学）和用于分子动力学的 AMBER 溶液或聚合酶中的 DNA 模拟。 DUPLEX 允许 不使用假设的情况下广泛搜索构象空间 关于最终的结构。分子动力学研究包括明确的 溶剂和盐，并提供动画，但在其方面受到更多限制 搜索。分子动力学轨迹产生的结构集合将 用于计算溶液中构象异构体之间的自由能差异，以及 聚合酶-引物-模板复合物的结合自由能。