RNA三级复杂结构中离子特异性结合的研究

RNAs are highly charged polyanionic biomolecules, and metal ion binding is critical for RNA folding into compact and active 3-dimensional structures, especially multivalent ions such as Mg2+. There are two ways for ion binding to RNAs: one is the diffusive binding, i.e., the majority of ions would keep hydrated and are territorially bound in the vicinity of RNAs; the other is the specific binding, i.e., a very small amount of ions can become dehydrated and binding to certain specific sites in RNAs. Recent experiments showed that the ion specific binding may be essential for the folding into specific 3-dimensional structure, the structure stability and the functions of RNAs. Due to the complex interface effect between RNA and solvent and the strong correlations between multivalent ions, the understanding and predictions on the roles of specific ion binding in RNA folding is still in the initial stage. In this project, taking into account the ion dehydrated/specific binding effects, we will extend our tightly bound ion model developed previously for treating ion diffusive binding to nucleic acids. With the use of the extended tightly bound ion model, Monte Carlo and all-atom molecular dynamics methods, we will investigate the roles of ion specific binding in RNA tertiary folding, by predicting binding sites and binding thermodynamics, and the effects of structural flexibility and ion concentrations. Our predictions will be compared with the available experiments, and then will reveal the specific role of ion specific binding in RNA tertiary folding. This project would enable the comprehensive understanding on the role and mechanism of ion specific binding in RNA tertiary structure folding.

RNA带有高密度负电荷，金属离子对其形成紧凑的三级功能结构有重要影响，特别是高价Mg2+。离子作用方式主要有两种：一是游离凝聚，大量离子会保持水合相对松散的凝聚在RNA附近；二是特异性结合，少数离子会脱水结合在RNA的特定部位。近来实验表明，离子特异性结合可能对RNA折叠为特定的三级空间结构及其稳定性和功能有着本质贡献。由于RNA-水复杂的界面性质和高价离子间的强关联作用，关于离子特异性结合效应的理解和预测还较肤浅。本项目中，我们将拓展我们提出的处理核酸-离子游离凝聚的紧束缚离子模型来处理离子脱水结合，并将结合蒙特卡洛和全原子分子动力学等方法全面研究RNA三级结构中离子的特异性结合，包括预测离子结合位点和结合热力学以及其中的RNA柔性和离子浓度效应等，预测将与相关实验比较，进而揭示RNA三级折叠中离子特异性结合的作用。本项目将促进对RNA三级结构折叠中离子特异性结合效应及其机制的全面理解。

RNA是具有重要生物功能并具有复杂结构的生物大分子，由于RNA带有高密度的负电荷，离子结合对于RNA结构、热力学、柔性均至关重要。本项目围绕RNA-离子结合以及RNA结构折叠中的离子效应，进行了如下工作：（1）建立了考虑离子效应和温度效应的RNA结构预测模型，此模型有效的把结构预测以及热力学与其中的离子效应结合在一起，并成功预测的RNA结构包括各种发夹结构、双链结构、假结结构等三维结构、热力学及其中的离子效应；（2）利用全原子分子动力学和蒙特卡洛模拟，从微观层面探究了RNA折叠、DNA凝聚中离子媒介有效折叠驱动力以及多体相互作用；（3）导出了描述RNA周围离子分布的泊松-玻尔兹曼理论的适用范围的经验公式，并进一步提出了具有他人使用价值的模拟混合单价/双价离子-核酸系统分配离子的普适方法；（4）揭示了短链DNA螺旋具有高柔性及其中离子效应的微观机制，并从微观层面揭示了RNA螺旋和DNA螺旋柔性间显著区别的原因。项目已发表SCI论文13篇，包括一区、二区刊物论文9篇，并有后续成果投寄。