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：(申请人提供)人类人口经常暴露在 与大量环境化学物质有关：其中一些可能引发癌症 而其他的，只是在结构上略有不同，是无害的。一个突出的问题 致癌物发挥作用的途径是通过某种方式与DNA反应 这会导致一个重要的细胞靶点发生突变。对机制的洞察 致癌物损伤的DNA产生突变的方式是必要的 识别潜在的危险物质。在这个项目中，密集型计算机 建模被用来探索这一过程。 我们在这里的努力特别针对移码突变，其 对癌症发生的贡献可能被低估了。特别是， 我们将尝试将化学结构与体内诱变效果联系起来 滑移/错位理论的框架。这一理论已经成功地 解释了许多移码突变的序列依赖性。我们会工作的 用四种芳香胺，一个化学类别的成员已经证明了 具有诱导移帧的特殊能力。我们的精选包括 乙酰氨基荧烯(AAF)，因为基于广泛的数据而被选择 关于它的致突变性，2-amino-1-methyl-6-phenylimidazo(4，5-b)pyridine (PhIP)和2-氨基-3-甲基咪唑(4，5-f)喹啉(IQ)，致癌物质 在烹调富含蛋白质的食物和1-氨基比林(AP)时形成的 柴油机尾气中常见污染物的转化产物， 城市空气颗粒物，以及其他一些来源。 我们将跟踪修饰的DNA引物-模板复合体的行为 继续执行扩展、堵塞和/或未对齐的步骤 选择适合其晶体结构的聚合酶的活性中心 都是可用的。我们的方法包括使用程序双工(用于 DNA修饰的分子力学)和用于分子动力学的琥珀 用溶液或聚合酶中的DNA进行模拟。双面打印允许 不使用假设的构象空间的广泛搜索 关于最终的结构。分子动力学研究包括显式 溶剂和盐，并提供动画，但在其更多的限制 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之间的自由能差，以及 聚合酶-引物-模板复合体的结合自由能。