Institute of Biophysics of the Czech Academy of Sciences, Královopolská 135 , 612 65 Brno , Czech Republic.
UCL School of Pharmacy, 29-39 Brunswick Square , London WC1N 1AX , U.K.
J Chem Theory Comput. 2018 Oct 9;14(10):5011-5026. doi: 10.1021/acs.jctc.8b00543. Epub 2018 Sep 28.
The NMR solution structures of human telomeric (Htel) G-quadruplexes (GQs) are characterized by the presence of two lateral loops complemented by either diagonal or propeller loops. Bases of a given loop can establish interactions within the loop as well as with other loops and the flanking bases. This can lead to a formation of base alignments above and below the GQ stems. These base alignments are known to affect the loop structures and relative stabilities of different Htel GQ folds. We have carried out a total of 217 μs of classical (unbiased) molecular dynamics (MD) simulations starting from the available solution structures of Htel GQs to characterize structural dynamics of the lateral and diagonal loops, using several recent AMBER DNA force-field variants. As the loops are involved in diverse stacking and H-bonding interactions, their dynamics is slow, and extended sampling is required to capture different conformations. Nevertheless, although the simulations are far from being quantitatively converged, the data suggest that multiple 10 μs-scale simulations can provide a quite good assessment of the loop conformational space as described by the force field. The simulations indicate that the lateral loops may sample multiple coexisting conformations, which should be considered when comparing simulations with the NMR models as the latter include ensemble averaging. The adenine-thymine Watson-Crick arrangement was the most stable base pairing in the simulations. Adenine-adenine and thymine-thymine base pairs were also sampled but were less stable. The data suggest that the description of lateral and diagonal GQ loops in contemporary MD simulations is considerably more realistic than the description of propeller loops, though definitely not flawless.
人端粒（Htel）G-四链体（GQs）的 NMR 溶液结构的特点是存在两个侧环，由对角或推进环补充。给定环的碱基可以在环内以及与其他环和侧翼碱基建立相互作用。这可能导致 GQ 茎上方和下方的碱基排列。众所周知，这些碱基排列会影响不同 Htel GQ 折叠的环结构和相对稳定性。我们总共进行了 217 μs 的经典（无偏）分子动力学（MD）模拟，从现有的 Htel GQ 溶液结构开始，使用几种最近的 AMBER DNA 力场变体来表征侧环和对角环的结构动力学。由于环参与了不同的堆积和氢键相互作用，它们的动力学较慢，需要扩展采样来捕获不同的构象。然而，尽管模拟远未达到定量收敛，但数据表明，多个 10 μs 规模的模拟可以很好地评估力场描述的环构象空间。模拟表明，侧环可能会采样多个共存的构象，在将模拟与 NMR 模型进行比较时应考虑到这一点，因为后者包括集合平均。在模拟中，腺嘌呤-胸腺嘧啶 Watson-Crick 排列是最稳定的碱基配对。腺嘌呤-腺嘌呤和胸腺嘧啶-胸腺嘧啶碱基对也被采样，但不太稳定。数据表明，当代 MD 模拟中侧环和对角 GQ 环的描述比推进环的描述要现实得多，尽管肯定不是完美的。
