Shandong Provincial Key Laboratory of Biophysics, Institute of Biophysics, Dezhou University, Dezhou 253023, China.
National Laboratory of Solid State Microstructure, Department of Physics, and Collaborative Innovation Center of Advanced Microstructures, Nanjing University, Nanjing 210093, China.
J Chem Phys. 2018 May 28;148(20):204107. doi: 10.1063/1.5028498.
Structure-based models or Gō-like models, which are built from one or multiple particular experimental structures, have been successfully applied to the folding of proteins and RNAs. Recently, a variant termed the hybrid atomistic model advances the description of backbone and side chain interactions of traditional structure-based models, by borrowing the description of local interactions from classical force fields. In this study, we assessed the validity of this model in the folding problem of human telomeric DNA G-quadruplex, where local dihedral terms play important roles. A two-state model was developed and a set of molecular dynamics simulations was conducted to study the folding dynamics of sequence Htel24, which was experimentally validated to adopt two different (3 + 1) hybrid G-quadruplex topologies in K solution. Consistent with the experimental observations, the hybrid-1 conformation was found to be more stable and the hybrid-2 conformation was kinetically more favored. The simulations revealed that the hybrid-2 conformation folded in a higher cooperative manner, which may be the reason why it was kinetically more accessible. Moreover, by building a Markov state model, a two-quartet G-quadruplex state and a misfolded state were identified as competing states to complicate the folding process of Htel24. Besides, the simulations also showed that the transition between hybrid-1 and hybrid-2 conformations may proceed an ensemble of hairpin structures. The hybrid atomistic structure-based model reproduced the kinetic partitioning folding dynamics of Htel24 between two different folds, and thus can be used to study the complex folding processes of other G-quadruplex structures.
基于结构的模型或 Gō 样模型，是由一个或多个特定的实验结构构建而成的，已经成功地应用于蛋白质和 RNA 的折叠。最近，一种称为杂化原子模型的变体通过从经典力场中借用局部相互作用的描述，改进了传统基于结构模型的主链和侧链相互作用的描述。在这项研究中，我们评估了该模型在人端粒 DNA G-四链体折叠问题中的有效性，其中局部二面角项起着重要作用。开发了一个两态模型，并进行了一组分子动力学模拟，以研究序列 Htel24 的折叠动力学，该序列在 K 溶液中已被实验验证为采用两种不同的（3 + 1）杂化 G-四链体拓扑结构。与实验观察一致，发现杂化-1构象更稳定，杂化-2构象在动力学上更有利。模拟表明，杂化-2构象以更高的协同方式折叠，这可能是它在动力学上更容易接近的原因。此外，通过构建马尔可夫状态模型，鉴定出两个四联体 G-四链体状态和一个错误折叠状态作为使 Htel24 折叠过程复杂化的竞争状态。此外，模拟还表明，杂化-1和杂化-2构象之间的转变可能经过一系列发夹结构。杂化原子结构基于模型再现了 Htel24 在两种不同折叠之间的动力学分区折叠动力学，因此可用于研究其他 G-四链体结构的复杂折叠过程。
