基于弹性和复杂网络模型的内向整流型钾通道Kir3.2的动力学及关键位点研究
Study on the Kinetics and Key Sites of Inward Rectifier Potassium Channel Kir3.2 Based on the Elastic Network and Complex Network Models

内向整流型钾通道蛋白Kir3.2能够调节钾离子的跨膜流动，具有重要的生理功能。由于其与神经和心肌系统的疾病相关，因此是一个重要的药物靶点。为研究该通道的动力学和功能性关键位点，我们首先利用高斯网络模型(GNM)对该通道进行建模，分析其结构的柔性，及各功能区域间的运动相关性；然后，构建运动相关性加权的复杂网络模型，通过依次敲除节点获得网络特征路径长度的变化来识别关键位点。结果发现，GNM重现了通道各区域的柔性；界面螺旋、跨膜螺旋和CTD区域间存在显著的运动正相关，这促进了通道与配体的结合和结构的稳定；所识别的关键残基对通道的激活、结构的稳定和变构信号交流起重要作用。本工作有助于加强对Kir3.2通道工作机制的理解，所识别的功能位点可为药物设计提供有价值的信息。
The inward rectifier potassium channel Kir3.2 can regulate the flow of potassium ions across the cell membrane, playing important physiological functions. Due to its association with diseases of the nervous and myocardial systems, it is an important target for drug design. To study its kinetics and functional key sites, we first construct its GNM model, analyze the structural flexibility and the mo-tion correlations between different functional regions. Then, the motion correlation-weighted com-plex network model is constructed, and the key sites are identified in terms of the changes of char-acteristic path lengths upon the nodes knocked one by one. The results found that the GNM model reproduces the flexibilities of different functional regions; evident positive correlations exist among the interfacial helices, transmembrane helices and CTD regions, which promotes channel-ligand binding and structural stability; the identified key residues play an important role in channel acti-vation, structural stability and signal communication. This work helps to enhance the understand-ing of Kir3.2 channel’s working mechanism, and the identified key sites can provide valuable in-formation for drug design.