Multiscale Simulations of Human Telomeric G-Quadruplex DNA
Multiscale Simulations of Human Telomeric G-Quadruplex DNA
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DOI：
10.1021/jp5103274
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发表时间：
2015-01-08
影响因子：
3.3
通讯作者：
Ulicny, Jozef
中科院分区：
文献类型：
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作者：
Rebic, Matus;Mocci, Francesca;Ulicny, Jozef
我们提出了一个粗粒（CG）模型的人类端粒G-四链体，使用逆蒙特卡罗（IMC）和迭代玻尔兹曼反演（IBI）技术内实现的软件包称为MagiC。作为起始点，2 HY 9人端粒[3 + 1]杂合体（26个核碱基序列）进行1 μ s长的原子分子动力学（MD）模拟而建模。所选择的四链体包括两种类型的环和可以在四链体中发现的鸟嘌呤链的相对取向的所有可能的组合。每个核苷酸一个珠子模型的有效CG潜力已经从该参考系统的径向分布函数中开发出来。所得到的电位明确考虑到与反离子的相互作用，而溶剂的影响包括隐含。所获得的CG模型的四链体的结构特性提供了一个完美的匹配，从参考原子的MD模拟。然后使用相同的一组相互作用势在CG水平上模拟另一种可以由人端粒DNA序列形成的四链体拓扑结构（PDB id 1 KF 1）。该四链体与2 HY 9在环拓扑结构和G链相对取向上不同。1 KF 1的CG MD模拟结果非常令人鼓舞，并表明基于2 HY 9的CG模型可以用于模拟具有不同拓扑结构的四路复用器。CG模型被进一步应用于由1 KF 1四链体结构重复20次形成的更高阶的人端粒四链体。在所有情况下，开发的模型，据我们所知，这是第一个模型的四链体在CG水平的文献中提出的，再现的主要结构特征非常好。
We present a coarse-grain (CG) model of human telomeric G-quadruplex, obtained using the inverse Monte Carlo (IMC) and iterative Boltzmann inversion (IBI) techniques implemented within the software package called MagiC. As a starting point, the 2HY9 human telomeric [3 + 1] hybrid, a 26-nucleobase sequence, was modeled performing a 1 mu s long atomistic molecular dynamics (MD) simulation. The chosen quadruplex includes two kinds of loops and all possible combinations of relative orientations of guanine strands that can be found in quadruplexes. The effective CG potential for a one bead per nucleotide model has been developed from the radial distribution functions of this reference system. The obtained potentials take into account explicitly the interaction with counterions, while the effect of the solvent is included implicitly. The structural properties of the obtained CG model of the quadruplex provided a perfect match to those resulting from the reference atomistic MD simulation. The same set of interaction potentials was then used to simulate at the CG level another quadruplex topology (PDB id 1KF1) that can be formed by the human telomeric DNA sequence. This quadruplex differs from 2HY9 in the loop topology and G-strand relative orientation. The results of the CG MD simulations of 1KF1 are very encouraging and suggest that the CG model based on 2HY9 can be used to simulate quadruplexes with different topologies. The CG model was further applied to a higher order human telomeric quadruplex formed by the repetition, 20 times, of the 1KF1 quadruplex structure. In all cases, the developed model, which to the best of our knowledge is the first model of quadruplexes at the CG level presented in the literature, reproduces the main structural features remarkably well.