Temperature-induced melting of double-stranded DNA in the absence and presence of covalently bonded antitumour drugs: insight from molecular dynamics simulations.
Temperature-induced melting of double-stranded DNA in the absence and presence of covalently bonded antitumour drugs: insight from molecular dynamics simulations.
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DOI：
10.1093/nar/gkr512
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发表时间：
2011-10
影响因子：
14.9
通讯作者：
Gago F
中科院分区：
文献类型：
--
作者：
Bueren-Calabuig JA;Giraudon C;Galmarini CM;Egly JM;Gago F
在不存在和存在结合配体的情况下双链（ds）DNA分子的解链温度的差异可以提供关于由配体结合带来的稳定化的实验信息。通过模拟序列5′-d（TAATAACGGATTATT）·5′-d（AATAATCCGTTATTA）双链体在0.1M NaCl水溶液中400 K的动力学行为，我们在<200 ns的时间内详细地表征了其完整的热变性曲线。在中心CGG三联体的两侧观察到显著的不对称性，并且链分离过程显示出受到原型链间交联剂丝裂霉素C或单官能四氢异喹啉trabectedin（Yondelis®）、Zepissis ®和PM 01183 ®的小沟中的键合的强烈影响。渐进的螺旋解压缩清楚地散布着一些再退火事件，这在含有单加合物的寡核苷酸中最明显，其在模拟结束时在中心区域保持平均6 bp。这些显著差异证明了这些药物稳定dsDNA、阻止复制和转录叉以及募集DNA修复蛋白的能力。这种稳定化，定量在这里的未中断的碱基对，支持这些单加合物可以在功能上模拟DNA链间交联的观点。
The difference in melting temperature of a double-stranded (ds) DNA molecule in the absence and presence of bound ligands can provide experimental information about the stabilization brought about by ligand binding. By simulating the dynamic behaviour of a duplex of sequence 5′-d(TAATAACGGATTATT)·5′-d(AATAATCCGTTATTA) in 0.1 M NaCl aqueous solution at 400 K, we have characterized in atomic detail its complete thermal denaturation profile in <200 ns. A striking asymmetry was observed on both sides of the central CGG triplet and the strand separation process was shown to be strongly affected by bonding in the minor groove of the prototypical interstrand crosslinker mitomycin C or the monofunctional tetrahydroisoquinolines trabectedin (Yondelis®), Zalypsis® and PM01183®. Progressive helix unzipping was clearly interspersed with some reannealing events, which were most noticeable in the oligonucleotides containing the monoadducts, which maintained an average of 6 bp in the central region at the end of the simulations. These significant differences attest to the demonstrated ability of these drugs to stabilize dsDNA, stall replication and transcription forks, and recruit DNA repair proteins. This stabilization, quantified here in terms of undisrupted base pairs, supports the view that these monoadducts can functionally mimic a DNA interstrand crosslink.
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影响因子：
14.9
作者：
Marco E;Negri A;Luque FJ;Gago F
通讯作者：
Gago F
影响因子：
64.5
作者：
Bustamante C;Cheng W;Mejia YX
通讯作者：
Mejia YX
影响因子：
4.4
作者：
JORGENSEN, WL;CHANDRASEKHAR, J;KLEIN, ML
通讯作者：
KLEIN, ML
DOI：
10.1073/pnas.2036378100
发表时间：
2003-11-25
影响因子：
11.1
作者：
Hagan, MF;Dinner, AR;Chakraborty, AK
通讯作者：
Chakraborty, AK
影响因子：
4.4
作者：
Drukker, K;Wu, GS;Schatz, GC
通讯作者：
Schatz, GC