Conformation of amine-modified DNA: 2-aminofluorene- and 2-(acetylamino)fluorene-modified deoxydinucleoside monophosphates with all possible nearest neighbors. A comparison of search and optimization methods.
Conformation of amine-modified DNA: 2-aminofluorene- and 2-(acetylamino)fluorene-modified deoxydinucleoside monophosphates with all possible nearest neighbors. A comparison of search and optimization methods.
复制标题
胺修饰 DNA 的构象：2-氨基芴和 2-(乙酰氨基)芴修饰的脱氧二核苷单磷酸与所有可能的最近邻居。
DOI：
10.1021/tx00038a018
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发表时间：
1994
影响因子：
4.1
通讯作者：
Broyde,S
中科院分区：
文献类型：
--
作者：
Shapiro,R;Sidawi,D;Miao,YS;Hingerty,BE;Schmidt,KE;Moskowitz,J;Broyde,S
尽管复制叉的重要部分以单链DNA的形式存在，但关于致癌物和诱变剂对单链构象的影响知之甚少。采用扭转角空间分子力学程序DUPLEX，采用势能最小化的大规模构象搜索方法，研究了鸟嘌呤上带有2-氨基芴（AF）或2-乙酰氨基芴（AAF）修饰的16个脱氧二核苷单磷酸的构象.因此，我们已经检查了3 '和5'修饰的效果，乙酰基的存在或不存在，以及在每种情况下四个不同邻居的效果。乙酰基的主要作用似乎是使修饰鸟嘌呤的反构象（以及在较小程度上的边界反构象）不稳定。这在S '-取代的二聚体中并不重要，其中一种构象类型在AAF和AF加合物的低能结构中占主导地位：它是右手的，具有顺鸟嘌呤，不完美的碱基-碱基堆叠，以及芴与3'-糖接触。在3 '-取代系列中观察到更大的分歧。AAF取代的3 '-加合物主要表现出良好的碱基-芴堆积，其中顺鸟嘌呤与5'-糖接触。AF取代的3 '-加合物具有多种结构，包括碱基-碱基和致癌物-碱基的堆积形式。遇到了两种新形式[d（ApG-AF）和d（GpG-AF）的全局最小值]，其不寻常的结构表明具有致突变能力。为了解决多个minimumproblem，我们进行了我们的搜索构象空间使用两种alternativeoptimization方法，也采用不同的搜索策略。我们使用的鲍威尔算法，BOTM，与选择的旋转异构体组合的起始构象，和模拟退火（SA）的方法，与随机或任意startingconformations。虽然这两种方法在确定最重要的结构方面都是有效的，但SA比BOTM更成功地定位了低能结构。
Although a significant part of the replication fork exists as single-stranded DNA, little is known about the effectof carcinogens and mutagens on single-strand conformation. Large-scale conformational searches with potential energy minimization, using the torsion anglespace molecular mechanics program DUPLEX, were employed to explore the conformationof all 16 deoxydinucleoside monophosphates bearing 2-aminofluorene (AF) or 2-(acetylamino) fluorene (AAF) modification on guanine. We have thus examined the effectof 3'versus 5'modification, the presence or absence of the acetyl group, and the effectof four different neighbors in each case. The principal effect of the acetyl groupappeared to be thedestabilization of anti (and, to a lesser degree, borderline anti) conformations for modified guanine. This mattered little in the S'-substituted dimers, where one conformational type predominated in the low-energy structures for the adducts of both AAF and AF: It was right-handed, with syn-guanine, imperfect base-base stacking, and fluorene to 3'-sugar contacts. Greater divergence was seen in the 3'-substituted series. The AAF-substituted 3'-adducts primarily displayed good base-fluorene stacking, with syn-guanine in contact with the 5'-sugar. The AF-substituted 3'-adducts displayed a variety of structures which included base-base and carcinogen-base stacked forms. Two novel forms were encountered [global minima for d (ApG-AF) and d (GpG-AF)], whose unusual structures suggest mutagenic capability. In orderto address the multiple minimumproblem, we conducted our searches of conformation space using two alternativeoptimization methods that also employ differing search strategies. We used the Powell algorithm, BOTM, with starting conformations that are selected combinations of rotamers, and the method of simulated annealing (SA), with random or arbitrary startingconformations. While both approaches were effective in defining the most important structures, SA was more successful than BOTM inlocating the structures of lowestenergy.