Molecular modeling and biophysical analysis of the c-MYC NHE-III1 silencer element
Molecular modeling and biophysical analysis of the c-MYC NHE-III1 silencer element
复制标题
DOI：
10.1007/s00894-007-0254-z
复制
发表时间：
2008-02-01
影响因子：
2.2
通讯作者：
Lewis, Edwin A.
中科院分区：
文献类型：
--
作者：
Cashman, Derek J.;Buscaglia, Robert;Lewis, Edwin A.
在几个癌基因的启动子区域中的G-四链体和i-基序形成序列显示出作为癌基因调控的靶点的希望。在这项研究中，从两个39个碱基的互补序列中创建了c-MYC NHE-III 1（核酸酶超敏元件III 1）的分子模型。这里模拟的NHE由聚嘌呤分子内G-四链体和聚嘧啶分子内i-基序结构的单折叠构象异构体组成，两侧是短双链体DNA序列。G-Quadruplex基于c-MYC 1：2：1环异构体的已发表NMR结构数据。i-Motif结构是理论上的（具有五个胞嘧啶-胞嘧啶对），其中中心插入的胞嘧啶核心相互作用基于四分子[d（A（2）C（4））（4）]模型i-Motif获得的NMR结构数据。环结构是c-MYC i基序环的计算机模拟预测。卟啉meso-四（N-甲基-4-吡啶基）卟啉（TMPyP 4）以及邻位和Meta类似物TMPyP 2和TMPyP 3对接到完整c-MYC NHE中的六个不同位置。比较药物与NHE和分离的G-四链体和i-Motif结构的结合。使用分子动力学技术模拟了100 ps的NHE模型，并计算了所有对接相互作用的DNA和卟啉之间的非键合相互作用能。
G-Quadruplex and i-Motif-forming sequences in the promoter regions of several oncogenes show promise as targets for the regulation of oncogenes. In this study, molecular models were created for the c-MYC NHE-III1 (nuclease hypersensitivity element III1) from two 39-base complementary sequences. The NHE modeled here consists of single folded conformers of the polypurine intramolecular G-Quadruplex and the polypyrimidine intramolecular i-Motif structures, flanked by short duplex DNA sequences. The G-Quadruplex was based on published NMR structural data for the c-MYC 1:2:1 loop isomer. The i-Motif structure is theoretical (with five cytosine-cytosine pairs), where the central intercalated cytosine core interactions are based on NMR structural data obtained for a tetramolecular [d(A(2)C(4))(4)] model i-Motif. The loop structures are in silico predictions of the c-MYC i-motif loops. The porphyrin meso-tetra(N-methyl-4-pyridyl)porphine (TMPyP4), as well as the ortho and meta analogs TMPyP2 and TMPyP3, were docked to six different locations in the complete c-MYC NHE. Comparisons are made for drug binding to the NHE and the isolated G-Quadruplex and i-Motif structures. NHE models both with and without bound cationic porphyrin were simulated for 100 ps using molecular dynamics techniques, and the non-bonded interaction energies between the DNA and porphyrins calculated for all of the docking interactions.