AF AND AAF MODIFIED DNA STRUCTURES--MUTAGENIC RELEVANCE

AF 和 AAF 修饰的 DNA 结构——突变相关性

• 批准号: 2769970
• 负责人: Suse Broyde
• 金额: $ 13.25万
• 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 2001-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2769970
• 关键词: DNA damage; DNA replication; acetylaminofluorene; chemical models; computer simulation; conformation; molecular dynamics; nucleic acid sequence

We are using minimized potential energy calculations with our program DUPLEX and molecular dynamics simulations with AMBER to determine the most stable conformations of DNA segments modified by the prototype mutagenic aromatic amines: 2-aminofluorene and 2- acetylaminofluorene. An extensive literature describes the genetic effects of this pair, which have been termed "superb tools for the exploration of the mechanisms of carcinogenesis". Our underlying hypothesis is that the structures of such damaged DNAs contribute to their mutagenic potential, and that an understanding of the details of structure will ultimately enable us to predict many of the genetic effects of chemical mutagens. The DNA species that we will examine model the stages of replication that lead to a mutagenic outcome, according to current theories. During the past few years, hypotheses have emerged which provide possible rationales for frameshift mutations (deletions in particular) and some base substitutions, in terms of the specific structures involved at the replications fork. Effects of the base sequence surrounding the modification on the nature of the structure of a particular chemical lesion will also be assessed, to gain insight into the sequence preferences ("hot spots" for the various kinds of mutagenic change. The results of the computations will produce atomic resolution views of the structures, together with their energy rankings. We expect that an examination of the changes produced in DNA by adducts derived from these amines will allow us to identify a well defined number of characteristic alterations. Our efforts at this stage will largely involve DNA alone, but in a few cases (as computational resources permit) we shall examine DNA in a complex with a fragment of a polymerase. As we gain understanding of the changes in DNA produced by AF and AAF modification, we will test our hypothesis by comparing our data with the growing collection of data on site-specific mutagenesis on these substances, and predicting nutational effects not yet tested experimentally.

我们正在使用最小化势能计算 使用 AMBER 进行 DUPLEX 和分子动力学模拟编程 确定修饰后的 DNA 片段最稳定的构象 由原型诱变芳香胺：2-氨基芴和2- 乙酰氨基芴。 大量文献描述了遗传 这对的影响被称为“卓越的工具” 探索致癌机制”。我们的基础 假设这种受损 DNA 的结构有助于 它们的致突变潜力，以及对细节的了解 结构最终将使我们能够预测许多遗传因素 化学诱变剂的影响。 我们要检查的 DNA 物种 模拟导致突变结果的复制阶段， 根据目前的理论。 在过去的几年里，假设 已经出现，为移码提供了可能的理由 突变（特别是缺失）和一些碱基替换， 涉及复制叉的特定结构。 修饰周围的碱基序列对 特定化学损伤的结构性质也将是 评估，以深入了解序列偏好（“热点” 各种诱变。 结果 计算将产生结构的原子分辨率视图， 以及他们的能源排名。 我们期望进行审查 由这些胺衍生的加合物在 DNA 中产生的变化 将使我们能够识别明确定义的特征数量 变更。 我们现阶段的努力将主要涉及DNA， 但在少数情况下（在计算资源允许的情况下）我们将 用聚合酶片段检查复合物中的 DNA。 正如我们 了解 AF 和 AAF 产生的 DNA 变化 修改后，我们将通过将我们的数据与 越来越多的关于这些基因的位点特异性诱变的数据收集 物质，并预测尚未测试的章动效应 实验性地。