Stability of Two-Quartet G-Quadruplexes and Their Dimers in Atomistic Simulations
Stability of Two-Quartet G-Quadruplexes and Their Dimers in Atomistic Simulations
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DOI：
10.1021/acs.jctc.9b01068
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发表时间：
2020-06-09
影响因子：
5.5
通讯作者：
Sponer, Jiri
中科院分区：
文献类型：
--
作者：
Islam, Barira;Stadlbauer, Petr;Sponer, Jiri
G-四链体（GQs）是一种由富含鸟嘌呤的序列组成的四链非经典DNA和RNA结构。GQ的稳定性随着G-四重态的数目增加而增加，并且三个G-四重态通常形成稳定的GQ。然而，两个四重态GQ的稳定性是一个悬而未决的问题。为了了解两个四重GQ茎的内在稳定性，我们进行了一系列的无偏分子动力学（MD）模拟（505亩）的两个和四个四重DNA和RNA GQs，注意主要是平行链的安排。我们使用AMBER DNA parmOL 15和RNA parmOL 3力场，并测试了不同的离子和水模型。两个四重平行链的DNA GQ在所有的模拟中展开，而等价的RNA GQ在大多数模拟中是稳定的。由两个四重态GQ的两个堆叠单元组成的GQ对DNA和RNA都是稳定的。模拟表明，至少需要三个四联体来形成本质上稳定的全反平行链DNA GQ平行的两个四联体DNA GQ可能存在，如果基本上由另一个分子或结构元件稳定，包括多聚化。另一方面，我们预测可能会形成分离的RNA两四重平行GQ，尽管稳定性较弱。我们还表明，离子参数和水模型应谨慎选择，因为一些参数的组合可能会导致虚假的GQ茎不稳定。一些在迄今为止未被注意到的多个离子内的GQ的力场描述的局限性进行了讨论，这损害了模拟的能力，以充分捕捉的GQ稳定性的四重态的数量增加的影响。
G-quadruplexes (GQs) are four-stranded noncanonical DNA and RNA architectures that can be formed by guanine-rich sequences. The stability of GQs increases with the number of G-quartets, and three G-quartets generally form stable GQs. However, the stability of two-quartet GQs is an open issue. To understand the intrinsic stability of two-quartet GQ stems, we have carried out a series of unbiased molecular dynamics (MD) simulations (505 mu s in total) of two- and four-quartet DNA and RNA GQs, with attention paid mainly to parallel-stranded arrangements. We used AMBER DNA parmOL15 and RNA parmOL3 force fields and tested different ion and water models. Two-quartet parallel-stranded DNA GQs unfolded in all the simulations, while the equivalent RNA GQ was stable in most of the simulations. GQs composed of two stacked units of two-quartet GQs were stable for both DNA and RNA. The simulations suggest that a minimum of three quartets are needed to form an intrinsically stable all-anti parallel-stranded DNA GQ Parallel two-quartet DNA GQ may exist if substantially stabilized by another molecule or structural element, including multimerization. On the other hand, we predict that isolated RNA two-quartet parallel GQs may form, albeit being weakly stable. We also show that ionic parameters and water models should be chosen with caution because some parameter combinations can cause spurious instability of GQ stems. Some in-so-far unnoticed limitations of force-field description of multiple ions inside the GQs are discussed, which compromise the capability of simulations to fully capture the effect of increase in the number of quartets on the GQ stability.