Fast-Folding Pathways of the Thrombin-Binding Aptamer G-Quadruplex Revealed by a Markov State Model
Fast-Folding Pathways of the Thrombin-Binding Aptamer G-Quadruplex Revealed by a Markov State Model
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马尔可夫态模型揭示了凝血酶结合适体 G-四联体的快速折叠途径
DOI：
10.1016/j.bpj.2018.02.021
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发表时间：
2018-04-10
影响因子：
3.4
通讯作者：
Wang, Jihua
中科院分区：
文献类型：
--
作者：
Bian, Yunqiang;Song, Feng;Wang, Jihua
G-四链体结构参与许多重要的细胞过程。为了更好地理解它们的功能，了解它们折叠成功能性天然结构的机制是必要的。在这项工作中，我们研究了凝血酶结合适体G-四链体的折叠过程。通过耦合先进的采样方法和马尔可夫状态模型的计算范例，确定了四个折叠中间体，包括一个反平行的G-发夹，两个G-三链体结构，和一个双发夹构象。同样地，还观察到具有非天然分布的顺/反鸟嘌呤的错误折叠结构。基于这些状态，过渡路径分析揭示了三个快速折叠途径，沿着凝血酶结合适体将直接折叠到天然状态，没有证据表明潜在的非天然竞争构象。结果还表明，TGT-loop在折叠过程中起着重要作用。这项研究的结果可能会提供有关其他G-四链体结构的折叠的一般见解。
G-quadruplex structures participate in many important cellular processes. For a better understanding of their functions, knowledge of the mechanism by which they fold into the functional native structures is necessary. In this work, we studied the folding process of the thrombin-binding aptamer G-quadruplex. Enabled by a computational paradigm that couples an advanced sampling method and a Markov state model, four folding intermediates were identified, including an antiparallel G-hairpin, two G-triplex structures, and a double-hairpin conformation. Likewise, a misfolded structure with a nonnative distribution of syn/anti guanines was also observed. Based on these states, a transition path analysis revealed three fast-folding pathways, along which the thrombin-binding aptamer would fold to the native state directly, with no evidence of potential nonnative competing conformations. The results also showed that the TGT-loop plays an important role in the folding process. The findings of this research may provide general insight about the folding of other G-quadruplex structures.