AF AND AAF MODIFIED DNA STRUCTURES--MUTAGENIC RELEVANCE

我们使用最小势能计算， 程序DUPLEX和分子动力学模拟与琥珀 以确定修饰的DNA片段的最稳定构象 通过原型诱变芳香胺：2-氨基芴和2- 乙酰氨基芴。 大量文献描述了遗传学 这一对的影响，这已被称为“高超的工具， 探索致癌机制”。 我们的基本 一种假设是，这种受损DNA的结构有助于 他们的诱变潜力，并了解的细节， 结构将最终使我们能够预测许多基因 化学诱变剂的影响。 我们将要检验的DNA种类 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 为框架转换提供了可能的理论基础 突变（特别是缺失）和一些碱基取代， 复制分叉中涉及的特定结构的术语。 修饰周围的碱基序列对 特定化学损伤的结构的性质也将被 评估，以深入了解序列偏好（“热点”， 各种各样的诱变变化。 的结果 计算将产生结构的原子分辨率视图， 以及他们的能量排名。 我们希望， 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个明确的数字特征， 改变。 我们在这一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）， 用聚合酶的片段检测复合物中的DNA。 正如我们 了解AF和AAF产生的DNA变化 修改，我们将通过比较我们的数据来测试我们的假设， 越来越多的关于这些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.