Aromatic Amine DNA Structures--Mutagenic Relevance

芳香胺 DNA 结构--诱变相关性

• 批准号: 6915508
• 负责人: Suse Broyde
• 金额: $ 28.13万
• 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/6915508
• 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：（由申请方提供）人群常规暴露 大量的环境化学物质：其中一些可能会引发癌症 而另一些只是结构上略有不同，是无害的。一个突出 致癌物发挥作用的途径是与DNA反应， 导致一个重要的细胞目标发生突变深入了解机制 致癌物受损的DNA产生突变的过程， 识别潜在的危险物质。在这个项目中，密集型计算机 模型被用来探索这个过程。 我们在这里的努力特别针对移码突变， 对致癌作用的贡献可能被低估了。特别是，委员会认为， 我们将尝试将化学结构与 滑移/错位理论的框架。这一理论成功地 解释了许多移码突变的序列依赖性。我们将 与四种芳香胺一起，该化学类别的成员已被证明具有 诱导移码的特殊能力我们的选择包括 乙酰氨基芴（AAF），选择是因为基于广泛的数据 2-氨基-1-甲基-6-苯基咪唑（4，5-B）吡啶的致突变性 （PhIP）和2-氨基-3-甲基-咪唑并（4，5-f）喹啉（IQ）， 在烹饪富含蛋白质的食物时形成的1-氨基芘（AP）， 柴油机废气中常见污染物的转化产物， 城市空气颗粒物和其他一些来源。 我们将跟踪修饰的DNA引物-模板复合物的行为，因为它们 继续进行延伸、堵塞和/或未对准的步骤 选择的聚合酶的活性位点， 都是可用的。我们的方法包括使用程序DUPLEX（用于 分子力学与修饰的DNA）和分子动力学的AMBER 在溶液或聚合酶中进行DNA模拟。DUPLEX允许 不使用假设的构象空间的广泛搜索 关于最终结构。分子动力学研究包括显式 溶剂和盐，并提供动画，但在它们的用途上更受限制。 搜索分子动力学轨迹产生的结构， 用于计算溶液中构象异构体之间的自由能差，以及 聚合酶-引物-模板复合物的结合自由能。