Reweighting of molecular simulations with explicit-solvent SAXS restraints elucidates ion-dependent RNA ensembles.
Reweighting of molecular simulations with explicit-solvent SAXS restraints elucidates ion-dependent RNA ensembles.
复制标题
明确的溶剂SAXS限制的分子模拟的重新加权阐明了离子依赖性RNA合奏。
DOI：
10.1093/nar/gkab459
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发表时间：
2021-08-20
影响因子：
14.9
通讯作者：
Bussi G
中科院分区：
文献类型：
--
作者：
Bernetti M;Hall KB;Bussi G
小角度x射线散射（SAXS）实验越来越多地用于探测RNA结构。在过去的几年里，已经提出了一些与测量的SAXS强度和结构特征相关的正演模型，这些模型适用于模拟显式溶剂效应或溶质动力学。在这里，我们介绍了一种集成原子分子动力学模拟和SAXS实验的方法，以重建RNA结构集成，同时考虑RNA构象动力学和显式溶剂效应。我们的方案利用SAXS纯溶质正演模型和增强的采样方法对异质结构集合进行采样，而不需要实时提供实验信息。然后通过最大熵原理对生成的结构系综重新加权，以匹配多离子条件下的参考SAXS实验数据。重要的是，精确的显式溶剂正演模型在这个重加权阶段被使用。我们将这一框架应用于gtpase相关中心（一种参与蛋白质翻译的相关RNA分子），以阐明其离子依赖性构象集合。我们表明(a)溶剂和动力学对于重现实验SAXS数据至关重要；(b)由此产生的动力学系综包含扩展结构的离子依赖部分。
Small-angle X-ray scattering (SAXS) experiments are increasingly used to probe RNA structure. A number of forward models that relate measured SAXS intensities and structural features, and that are suitable to model either explicit-solvent effects or solute dynamics, have been proposed in the past years. Here, we introduce an approach that integrates atomistic molecular dynamics simulations and SAXS experiments to reconstruct RNA structural ensembles while simultaneously accounting for both RNA conformational dynamics and explicit-solvent effects. Our protocol exploits SAXS pure-solute forward models and enhanced sampling methods to sample an heterogenous ensemble of structures, with no information towards the experiments provided on-the-fly. The generated structural ensemble is then reweighted through the maximum entropy principle so as to match reference SAXS experimental data at multiple ionic conditions. Importantly, accurate explicit-solvent forward models are used at this reweighting stage. We apply this framework to the GTPase-associated center, a relevant RNA molecule involved in protein translation, in order to elucidate its ion-dependent conformational ensembles. We show that (a) both solvent and dynamics are crucial to reproduce experimental SAXS data and (b) the resulting dynamical ensembles contain an ion-dependent fraction of extended structures.
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