核酶上的离子凝聚具有位点特异性和折叠依赖性
Ion Condensation onto Ribozyme is Site-Specific and Fold-Dependent
摘要：
高度带电的RNA分子，每个磷酸携带单个负电荷，在没有离子的情况下，不能折叠成具有三级相互作用的明确定义的结构。对于核酶，已知二价阳离子比单价离子更有效地将它们驱动到紧凑状态，尽管Mg $^{2+}$离子对于催化活性是需要的。因此，离子如何与RNA相互作用与理解RNA折叠有关。通常认为，大多数离子是领土和非特异性结合的RNA，如所预测的反离子缩合（CIC）理论。在这里，我们使用模拟的${\it Azoarcus}$核酶，基于一个准确的粗粒度的三个网站的相互作用（TIS）模型，明确的二价和一价阳离子，离子凝聚是高度特异性的，并取决于核苷酸的位置。当核酶不形成三级相互作用时，即使在非常低的Mg $^{2+}$浓度下，磷酸基团和二价阳离子之间具有高配位的区域也是可辨别的。令人惊讶的是，这些区域还含有二级结构元件，这些二级结构元件随后在RNA的自组装中成核，这意味着离子凝聚是由折叠状态的结构决定的。这些结果与离子（一价和二价）与刚性带电杆的相互作用形成鲜明对比，其中离子凝聚是均匀的和位置无关的。这些差异是由于核酶在折叠时随着Mg $^{2+}$或Ca $^{2+}$浓度的增加而出现的剧烈的非单调形状波动。
英文摘要：
The highly charged RNA molecules, with each phosphate carrying a single negative charge, cannot fold into well-defined architectures with tertiary interactions, in the absence of ions. For ribozymes, divalent cations are known to be more efficient than monovalent ions in driving them to a compact state although Mg$^{2+}$ ions are needed for catalytic activities. Therefore, how ions interact with RNA is relevant in understanding RNA folding. It is often thought that most of the ions are territorially and non-specifically bound to the RNA, as predicted by the counterion condensation (CIC) theory. Here, we show using simulations of ${\it Azoarcus}$ ribozyme, based on an accurate coarse-grained Three Site Interaction (TIS) model, with explicit divalent and monovalent cations, that ion condensation is highly specific and depends on the nucleotide position. The regions with high coordination between the phosphate groups and the divalent cations are discernible even at very low Mg$^{2+}$ concentrations when the ribozyme does not form tertiary interactions. Surprisingly, these regions also contain the secondary structural elements that nucleate subsequently in the self-assembly of RNA, implying that ion condensation is determined by the architecture of the folded state. These results are in sharp contrast to interactions of ions (monovalent and divalent) with rigid charged rods in which ion condensation is uniform and position independent. The differences are explained in terms of the dramatic non-monotonic shape fluctuations in the ribozyme as it folds with increasing Mg$^{2+}$ or Ca$^{2+}$ concentration.
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