School of Computational Sciences, Korea Institute for Advanced Study, Seoul 130-722, South Korea.
J Chem Phys. 2013 Sep 28;139(12):121924. doi: 10.1063/1.4818594.
As a consequence of the rugged landscape of RNA molecules their folding is described by the kinetic partitioning mechanism according to which only a small fraction (φF) reaches the folded state while the remaining fraction of molecules is kinetically trapped in misfolded intermediates. The transition from the misfolded states to the native state can far exceed biologically relevant time. Thus, RNA folding in vivo is often aided by protein cofactors, called RNA chaperones, that can rescue RNAs from a multitude of misfolded structures. We consider two models, based on chemical kinetics and chemical master equation, for describing assisted folding. In the passive model, applicable for class I substrates, transient interactions of misfolded structures with RNA chaperones alone are sufficient to destabilize the misfolded structures, thus entropically lowering the barrier to folding. For this mechanism to be efficient the intermediate ribonucleoprotein complex between collapsed RNA and protein cofactor should have optimal stability. We also introduce an active model (suitable for stringent substrates with small φF), which accounts for the recent experimental findings on the action of CYT-19 on the group I intron ribozyme, showing that RNA chaperones do not discriminate between the misfolded and the native states. In the active model, the RNA chaperone system utilizes chemical energy of adenosine triphosphate hydrolysis to repeatedly bind and release misfolded and folded RNAs, resulting in substantial increase of yield of the native state. The theory outlined here shows, in accord with experiments, that in the steady state the native state does not form with unit probability.
由于 RNA 分子的崎岖景观，它们的折叠是通过动力学分区机制来描述的，根据该机制，只有一小部分（φF）达到折叠状态，而其余分子的分数则在动力学上被困在错误折叠的中间体中。从错误折叠状态到天然状态的转变可能远远超过生物学相关时间。因此，体内 RNA 折叠通常需要蛋白质辅助因子（称为 RNA 伴侣）的帮助，这些辅助因子可以使 RNA 从多种错误折叠结构中恢复。我们考虑了两种基于化学动力学和化学主方程的模型来描述辅助折叠。在被动模型中，适用于 I 类底物，错误折叠结构与 RNA 伴侣的瞬时相互作用足以使错误折叠结构不稳定，从而降低折叠的熵障碍。为了使该机制有效，RNA 与蛋白辅助因子之间的中间核糖核蛋白复合物应具有最佳的稳定性。我们还引入了一种主动模型（适用于φF 较小的严格底物），该模型解释了 CYT-19 对 I 组内含子核酶的作用的最新实验发现，表明 RNA 伴侣不会区分错误折叠和天然状态。在主动模型中，RNA 伴侣系统利用三磷酸腺苷水解的化学能反复结合和释放错误折叠和折叠的 RNA，从而显著增加天然状态的产率。这里概述的理论与实验一致，表明在稳态下，天然状态不会以单位概率形成。
