Elucidating molecular motion through structural and dynamic filters of energy-minimized conformer ensembles.
Elucidating molecular motion through structural and dynamic filters of energy-minimized conformer ensembles.
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DOI：
10.1021/jp409386t
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发表时间：
2014-02-20
期刊：
影响因子：
--
通讯作者：
Drobny GP
中科院分区：
文献类型：
--
作者：
Emani PS;Bardaro MF Jr;Huang W;Aragon S;Varani G;Drobny GP
复杂的RNA结构由通过柔性环连接的螺旋片段构成，所述柔性环自发移动并响应于小分子配体和蛋白质的结合。理解RNA的构象变异性需要表征相互连接的柔性结构域的耦合时间演化。为了阐明集体分子运动和探索的HIV-1 TAR RNA的构象景观，我们描述了一种新的方法，利用能量最小化的结构产生的程序“片段装配RNA与全原子细化（FARFAR）"。我们应用结构过滤器的形式的实验残余偶极耦合（RDC）选择一个子集的离散能量最小化的构象和进行主成分分析（PCA），以证实过滤子集的选择。我们使用这个结构的子集来计算溶液T1和T1ρ弛豫时间为13 C自旋在多个残基在不同的结构域的分子使用两个模拟协议，我们以前发表的。对于螺旋残基，我们将实验T1时间匹配到2%以内，将T1ρ时间匹配到小于10%以内。这些结果介绍了一个协议，以构建可行的动态轨迹的RNA分子，雅阁以及与实验NMR数据和支持的概念，这种小RNA的螺旋部分的运动可以描述为一个相对较少的离散构象交换超过1 μs的时间尺度。
Complex RNA structures are constructed from helical segments connected by flexible loops that move spontaneously and in response to binding of small molecule ligands and proteins. Understanding the conformational variability of RNA requires the characterization of the coupled time evolution of interconnected flexible domains. To elucidate the collective molecular motions and explore the conformational landscape of the HIV-1 TAR RNA, we describe a new methodology that utilizes energy-minimized structures generated by the program “Fragment Assembly of RNA with Full-Atom Refinement (FARFAR)”. We apply structural filters in the form of experimental residual dipolar couplings (RDCs) to select a subset of discrete energy-minimized conformers and carry out principal component analyses (PCA) to corroborate the choice of the filtered subset. We use this subset of structures to calculate solution T1 and T1ρ relaxation times for 13C spins in multiple residues in different domains of the molecule using two simulation protocols that we previously published. We match the experimental T1 times to within 2% and the T1ρ times to within less than 10% for helical residues. These results introduce a protocol to construct viable dynamic trajectories for RNA molecules that accord well with experimental NMR data and support the notion that the motions of the helical portions of this small RNA can be described by a relatively small number of discrete conformations exchanging over time scales longer than 1 μs.
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