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首页> 外文期刊>Journal of Molecular Biology >Molecular dynamics simulations of viral RNA polymerases link conserved and correlated motions of functional elements to fidelity.
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Molecular dynamics simulations of viral RNA polymerases link conserved and correlated motions of functional elements to fidelity.

机译：病毒RNA聚合酶的分子动力学模拟将功能元件的保守运动和相关运动与保真度联系起来。

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The viral RNA-dependent RNA polymerase (RdRp) is essential for multiplication of all RNA viruses. The sequence diversity of an RNA virus population contributes to its ability to infect the host. This diversity emanates from errors made by the RdRp during RNA synthesis. The physical basis for RdRp fidelity is unclear but is linked to conformational changes occurring during the nucleotide-addition cycle. To understand RdRp dynamics that might influence RdRp function, we have analyzed all-atom molecular dynamics simulations on the nanosecond timescale of four RdRps from the picornavirus family that exhibit 30-74% sequence identity. Principal component analysis showed that the major motions observed during the simulations derived from conserved structural motifs and regions of known function. The dynamics of residues participating in the same biochemical property, for example, RNA binding, nucleotide binding or catalysis, were correlated even when spatially distant on the RdRp structure. The conserved and correlated dynamics of functional structural elements suggest coevolution of dynamics with structure and function of the RdRp. Crystal structures of all picornavirus RdRps exhibit a template-nascent RNA duplex channel too small to fully accommodate duplex RNA. Simulations revealed opening and closing motions of the RNA and nucleoside triphosphate channels, which might be relevant to nucleoside triphosphate entry, inorganic pyrophosphate exit and translocation. A role for nanosecond timescale dynamics in RdRp fidelity is supported by the altered dynamics of the high-fidelity G64S derivative of PV RdRp relative to wild-type enzyme.
机译：病毒RNA依赖性RNA聚合酶（RdRp）对于所有RNA病毒的繁殖都是必不可少的。 RNA病毒种群的序列多样性有助于其感染宿主的能力。这种多样性源于RdRp在RNA合成过程中产生的错误。 RdRp保真度的物理基础尚不清楚，但与核苷酸加成周期中发生的构象变化有关。为了了解可能影响RdRp功能的RdRp动力学，我们分析了来自小核糖核酸病毒家族的四个RdRps的纳秒级时标的全原子分子动力学模拟，这些模拟显示出30-74％的序列同一性。主成分分析表明，在仿真过程中观察到的主要运动源自保守的结构图案和已知功能的区域。即使在RdRp结构上空间距离遥远，参与相同生化特性（例如RNA结合，核苷酸结合或催化）的残基的动力学也相关。功能结构元件的保守和相关动力学表明动力学与RdRp的结构和功能的共同进化。所有小核糖核酸病毒RdRps的晶体结构均显示出一个模板新生的RNA双链通道，该通道太小而无法完全容纳双链RNA。模拟显示RNA和核苷三磷酸通道的打开和关闭运动，这可能与核苷三磷酸进入，无机焦磷酸出口和易位有关。相对于野生型酶，PV RdRp的高保真度G64S衍生物的动力学变化支持了RdRp保真度中纳秒时间尺度动力学的作用。

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