Exploration of the folding dynamics of human telomeric G-quadruplex with a hybrid atomistic structure-based model
Exploration of the folding dynamics of human telomeric G-quadruplex with a hybrid atomistic structure-based model
复制标题
使用基于混合原子结构的模型探索人类端粒 G-四链体的折叠动力学
DOI：
10.1063/1.5028498
复制
发表时间：
2018-05-28
影响因子：
4.4
通讯作者：
Wang, Jihua
中科院分区：
文献类型：
--
作者：
Bian, Yunqiang;Ren, Weitong;Wang, Jihua
基于结构的模型或Go-like模型是由一个或多个特定的实验结构建立的，已经成功地应用于蛋白质和rna的折叠。最近，一种被称为混合原子模型的变体通过借用经典力场的局部相互作用描述，改进了传统基于结构的模型对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类端粒dna -四重体折叠问题中的有效性，其中局部二面体项起着重要作用。建立了双态模型，并进行了分子动力学模拟，研究了序列Htel24在K+溶液中采用两种不同（3 + 1）混合g -四复体拓扑结构的折叠动力学。与实验观察结果一致，杂种1构象更稳定，杂种2构象在动力学上更有利。模拟结果表明，杂合-2构象以更高的合作方式折叠，这可能是它在动力学上更容易接近的原因。此外，通过建立马尔可夫状态模型，将双四重g -四重态和错误折叠态识别为竞争态，使Htel24的折叠过程复杂化。此外，模拟还表明，杂合-1和杂合-2构象之间的转变可能是一个发夹结构的集合。基于混合原子结构的模型再现了Htel24在两种不同折叠之间的动力学分配折叠动力学，从而可用于研究其他g -四重结构的复杂折叠过程。AIP出版社出版。
Structure-based models or Go-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 telomericDNAG-quadruplex, where local dihedral terms play important roles. Atwo-state modelwas 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 hybrid1 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. Published by AIP Publishing.