Institute of Biophysics of the Czech Academy of Sciences, Královopolská 135, 612 65 Brno, Czech Republic.
Regional Centre of Advanced Technologies and Materials, Department of Physical Chemistry, Faculty of Science, Palacký University, 17. listopadu 12, 77146 Olomouc, Czech Republic.
Nucleic Acids Res. 2018 Sep 28;46(17):8754-8771. doi: 10.1093/nar/gky712.
We have carried out an extended set of standard and enhanced-sampling MD simulations (for a cumulative simulation time of 620 μs) with the aim to study folding landscapes of the rGGGUUAGGG and rGGGAGGG parallel G-hairpins (PH) with propeller loop. We identify folding and unfolding pathways of the PH, which is bridged with the unfolded state via an ensemble of cross-like structures (CS) possessing mutually tilted or perpendicular G-strands interacting via guanine-guanine H-bonding. The oligonucleotides reach the PH conformation from the unfolded state via a conformational diffusion through the folding landscape, i.e. as a series of rearrangements of the H-bond interactions starting from compacted anti-parallel hairpin-like structures. Although isolated PHs do not appear to be thermodynamically stable we suggest that CS and PH-types of structures are sufficiently populated during RNA guanine quadruplex (GQ) folding within the context of complete GQ-forming sequences. These structures may participate in compact coil-like ensembles that involve all four G-strands and already some bound ions. Such ensembles can then rearrange into the fully folded parallel GQs via conformational diffusion. We propose that the basic atomistic folding mechanism of propeller loops suggested in this work may be common for their formation in RNA and DNA GQs.
我们进行了一系列扩展的标准和增强采样 MD 模拟（累积模拟时间为 620 μs），旨在研究带有桨叶环的 rGGGUUAGGG 和 rGGGAGGG 平行 G-发夹（PH）的折叠景观。我们确定了 PH 的折叠和展开途径，该途径通过具有相互倾斜或垂直 G-链的交叉样结构（CS）与未折叠状态桥接，通过鸟嘌呤-鸟嘌呤氢键相互作用。寡核苷酸通过折叠景观中的构象扩散从无规卷曲状态到达 PH 构象，即通过从紧密的反平行发夹样结构开始的氢键相互作用的一系列重排。尽管孤立的 PH 似乎没有热力学稳定性，但我们建议 CS 和 PH 类型的结构在完整 GQ 形成序列的 RNA 鸟嘌呤四链体（GQ）折叠过程中充分存在。这些结构可能参与涉及所有四个 G-链和已经结合的一些离子的紧凑卷曲样集合。然后，这些集合可以通过构象扩散重新排列成完全折叠的平行 GQ。我们提出，本文中提出的桨叶环的基本原子折叠机制可能与其在 RNA 和 DNA GQ 中的形成有关。
