AF AND AAF MODIFIED DNA STRUCTURES--MUTAGENIC RELEVANCE

我们正在使用最小化势能计算 用Amber进行程序双工和分子动力学模拟 确定DNA修饰片段的最稳定构象 致突变芳香胺的原型：2-氨基荧烯和2-氨基-2 乙酰氨基荧烯。一篇广泛的文献描述了基因 这对人的影响，他们被称为“卓越的工具 对致癌机制的探索“。我们的基本观点 假说是这种受损DNA的结构有助于 它们的诱变潜力，以及对 结构最终将使我们能够预测许多基因 化学诱变剂的影响。我们将研究的DNA物种 对导致突变结果的复制阶段进行建模， 根据目前的理论。在过去的几年里，假设 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，在 复制分叉所涉及的特定结构的术语。 修饰周围的碱基序列对基因的影响 特定化学损伤的结构的性质也将是 进行评估，以深入了解序列首选项( 各种诱变的变化。评选结果 计算将产生结构的原子分辨率视图， 以及他们的能源排名。我们期待着对 脱氧核糖核酸由这些胺衍生的加合物在DNA中产生的变化 将使我们能够确定一系列定义明确的特征 改装。我们在这个阶段的努力将主要涉及DNA本身， 但在少数情况下(在计算资源允许的情况下)，我们将 检测含有聚合酶片段的复合体中的DNA。因为我们 了解房颤和房颤产生的DNA的变化 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定点突变的数据收集 物质，并预测尚未测试的章动效应 试验性的。

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.