Aromatic Amine DNA Structures--Mutagenic Relevance
芳香胺 DNA 结构--诱变相关性
基本信息
- 批准号:6915508
- 负责人:
- 金额:$ 28.13万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:
项目摘要
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。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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{{ truncateString('Suse Broyde', 18)}}的其他基金
Environmental DNA Lesions and Mutagenesis: Molecular Mechanisms of Lesion Recognition for Repair and Polymerase Bypass
环境 DNA 损伤和诱变:损伤识别修复和聚合酶旁路的分子机制
- 批准号:
10460604 - 财政年份:2016
- 资助金额:
$ 28.13万 - 项目类别:
Environmental Carcinogen-DNA Adducts: NER Recognition
环境致癌物-DNA 加合物:NER 识别
- 批准号:
9275988 - 财政年份:2016
- 资助金额:
$ 28.13万 - 项目类别:
Environmental DNA Lesions and Mutagenesis: Molecular Mechanisms of Lesion Recognition for Repair and Polymerase Bypass
环境 DNA 损伤和诱变:损伤识别修复和聚合酶旁路的分子机制
- 批准号:
10612958 - 财政年份:2016
- 资助金额:
$ 28.13万 - 项目类别:
Environmental DNA Lesions and Mutagenesis: Molecular Mechanisms of Lesion Recognition for Repair and Polymerase Bypass
环境 DNA 损伤和诱变:损伤识别修复和聚合酶旁路的分子机制
- 批准号:
10293848 - 财政年份:2016
- 资助金额:
$ 28.13万 - 项目类别:
STRUCTURAL STUDY OF A DNA ADDUCT DEVIRED FROM A TUMORIGENIC METABOLITE OF BENZO
苯并致瘤代谢产物 DNA 加合物的结构研究
- 批准号:
7956119 - 财政年份:2009
- 资助金额:
$ 28.13万 - 项目类别:
STRUCTURAL STUDY OF A DNA ADDUCT DEVIRED FROM A TUMORIGENIC METABOLITE OF BENZO
苯并致瘤代谢产物 DNA 加合物的结构研究
- 批准号:
7723185 - 财政年份:2008
- 资助金额:
$ 28.13万 - 项目类别:
STRUCTURAL STUDY OF A DNA ADDUCT DEVIRED FROM A TUMORIGENIC METABOLITE OF BENZO
苯并致瘤代谢产物 DNA 加合物的结构研究
- 批准号:
7601434 - 财政年份:2007
- 资助金额:
$ 28.13万 - 项目类别:
Aromatic Amine DNA Structures--Mutagenic Relevance
芳香胺 DNA 结构--诱变相关性
- 批准号:
6522395 - 财政年份:1997
- 资助金额:
$ 28.13万 - 项目类别:
DNA Lesion Structures: Mutagenicity and Repair
DNA 损伤结构:致突变性和修复
- 批准号:
7280349 - 财政年份:1997
- 资助金额:
$ 28.13万 - 项目类别:
DNA Lesion Structures: Mutagenicity and Repair
DNA 损伤结构:致突变性和修复
- 批准号:
7634396 - 财政年份:1997
- 资助金额:
$ 28.13万 - 项目类别:
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