Free energy landscapes of RNA/RNA complexes: With applications to snRNA complexes in spliceosomes
Free energy landscapes of RNA/RNA complexes: With applications to snRNA complexes in spliceosomes
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DOI：
10.1016/j.jmb.2005.12.014
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发表时间：
2006-03-17
影响因子：
5.6
通讯作者：
Chen, SJ
中科院分区：
文献类型：
--
作者：
Cao, S;Chen, SJ
我们开发了一个统计力学模型的RNA/RNA复合物的分子内和分子间的相互作用。作为该模型的一个应用，我们计算的自由能景观，它给出了所有可能的构象的完整分布，为U4/U6和U2/U6在主要剪接体和U4 atac/U6 atac和U12/U6 atac在次要剪接体。不同的snRNA实验发现了不同的结构，我们的自由能景观理论显示了为什么这些结构出现以及它们如何相互竞争。对于酵母U2/U6，该模型预测，两个不同的实验结构，四螺旋连接结构和含Ib的螺旋结构，实际上可以共存，并专门相互竞争。此外，能源景观建议可能的机制，剪接的构象转换。例如，我们的计算表明，同轴堆叠是必不可少的稳定酵母U2/U6的四螺旋连接。因此，可能通过蛋白质结合抑制共轴堆积可以激活从四螺旋连接到含螺旋Ib的结构的构象转换。此外，能量景观形状的变化给出了关于构象变化的信息。我们发现多个（天然的和错误折叠的）中间体通过碱基配对重排形成的snRNA复合物。例如，U2/U6的解折叠经历到功能性的错误折叠状态的转变，而在U12/U6 atac的解折叠中，发现功能性螺旋Ib是最后解折叠的螺旋，因此是最稳定的结构组分。此外，能量格局给出了所有可能的（功能性）中间体的稳定性，并且这些信息与剪接效率直接相关。
We develop a statistical mechanical model for RNA/RNA complexes with both intramolecular and intermolecular interactions. As an application of the model, we compute the free energy landscapes, which give the full distribution for all the possible conformations, for U4/U6 and U2/U6 in major spliceosome and U4atac/U6atac and U12/U6atac in minor spliceosome. Different snRNA experiments found contrasting structures, our free energy landscape theory shows why these structures emerge and how they compete with each other. For yeast U2/U6, the model predicts that the two distinct experimental structures, the four-helix junction structure and the helix Ib-containing structure, can actually coexist and specifically compete with each other. In addition, the energy landscapes suggest possible mechanisms for the conformational switches in splicing. For instance, our calculation shows that coaxial stacking is essential for stabilizing the four-helix junction in yeast U2/U6. Therefore, inhibition of the coaxial stacking possibly by protein-binding may activate the conformational switch from the four-helix junction to the helix Ib-containing structure. Moreover, the change of the energy landscape shape gives information about the conformational changes. We find multiple (native-like and misfolded) intermediates formed through base-pairing rearrangements in snRNA complexes. For example, the unfolding of the U2/U6 undergoes a transition to a misfolded state which is functional, while in the unfolding of U12/U6atac, the functional helix Ib is found to be the last one to unfold and is thus the most stable structural component. Furthermore, the energy landscape gives the stabilities of all the possible (functional) intermediates and such information is directly related to splicing efficiency.