RNA folding pathways in stop motion
RNA folding pathways in stop motion
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DOI：
10.1093/nar/gkw239
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发表时间：
2016-07-08
影响因子：
14.9
通讯作者：
Bussi, Giovanni
中科院分区：
文献类型：
--
作者：
Bottaro, Sandro;Gil-Ley, Alejandro;Bussi, Giovanni
我们介绍了一种预测 RNA 折叠途径的方法，并应用于最重要的 RNA 四环。该方法基于这样的思想：从高分辨率晶体结构中提取的三维片段的集合具有足够的异质性，足以描述亚稳态和中间态。首先通过与一组 RNA 四核苷酸的可用溶液核磁共振 (NMR) 数据进行定量比较来验证这些集合。值得注意的是，与通过将 NMR 与广泛的全原子分子动力学模拟进行比较获得的结果相比，该一致性更好。然后，我们提出了一种基于扩散图和马尔可夫模型的程序，使得可以从片段集合中获得反应路径及其相对概率。该方法适用于研究 GNRA 和 UNCG 家族所有四环的螺旋到环折叠途径。结果给出了与现有实验数据兼容的折叠机制的详细见解，并阐明了先前模拟研究中观察到的中间态的作用。该方法计算成本低廉，可用于研究任意构象转变。
We introduce a method for predicting RNA folding pathways, with an application to the most important RNA tetraloops. The method is based on the idea that ensembles of three-dimensional fragments extracted from high-resolution crystal structures are heterogeneous enough to describe metastable as well as intermediate states. These ensembles are first validated by performing a quantitative comparison against available solution nuclear magnetic resonance (NMR) data of a set of RNA tetranucleotides. Notably, the agreement is better with respect to the one obtained by comparing NMR with extensive all-atom molecular dynamics simulations. We then propose a procedure based on diffusion maps and Markov models that makes it possible to obtain reaction pathways and their relative probabilities from fragment ensembles. This approach is applied to study the helix-to-loop folding pathway of all the tetraloops from the GNRA and UNCG families. The results give detailed insights into the folding mechanism that are compatible with available experimental data and clarify the role of intermediate states observed in previous simulation studies. The method is computationally inexpensive and can be used to study arbitrary conformational transitions.