Department of Chemistry, New York University, New York, New York, United States of America.
PLoS Comput Biol. 2012;8(2):e1002368. doi: 10.1371/journal.pcbi.1002368. Epub 2012 Feb 16.
Riboswitches are RNAs that modulate gene expression by ligand-induced conformational changes. However, the way in which sequence dictates alternative folding pathways of gene regulation remains unclear. In this study, we compute energy landscapes, which describe the accessible secondary structures for a range of sequence lengths, to analyze the transcriptional process as a given sequence elongates to full length. In line with experimental evidence, we find that most riboswitch landscapes can be characterized by three broad classes as a function of sequence length in terms of the distribution and barrier type of the conformational clusters: low-barrier landscape with an ensemble of different conformations in equilibrium before encountering a substrate; barrier-free landscape in which a direct, dominant "downhill" pathway to the minimum free energy structure is apparent; and a barrier-dominated landscape with two isolated conformational states, each associated with a different biological function. Sharing concepts with the "new view" of protein folding energy landscapes, we term the three sequence ranges above as the sensing, downhill folding, and functional windows, respectively. We find that these energy landscape patterns are conserved in various riboswitch classes, though the order of the windows may vary. In fact, the order of the three windows suggests either kinetic or thermodynamic control of ligand binding. These findings help understand riboswitch structure/function relationships and open new avenues to riboswitch design.
Riboswitches 是通过配体诱导的构象变化来调节基因表达的 RNA。然而，序列如何决定基因调控的替代折叠途径尚不清楚。在这项研究中，我们计算了能量景观，这些景观描述了一系列序列长度的可及二级结构，以分析给定序列延伸到全长时的转录过程。与实验证据一致，我们发现大多数 riboswitch 景观可以根据序列长度分为三类，这取决于构象簇的分布和障碍类型：在遇到底物之前，具有不同构象平衡的低障碍景观；无障碍景观，其中直接的、主导的“下坡”途径到最小自由能结构是明显的；以及具有两个孤立构象状态的障碍主导景观，每个状态都与不同的生物学功能相关。与蛋白质折叠能量景观的“新观点”共享概念，我们将上述三个序列范围分别称为感应、下坡折叠和功能窗口。我们发现，这些能量景观模式在各种 riboswitch 类中是保守的，尽管窗口的顺序可能会有所不同。事实上，三个窗口的顺序表明配体结合的是动力学控制还是热力学控制。这些发现有助于理解 riboswitch 的结构/功能关系，并为 riboswitch 的设计开辟了新途径。
