Structural and Informatics Basis of Channel Protein Interactions

将诱导同源性建模方法与低同源区的演绎分子模拟方法相结合，建立了通道蛋白三级结构模型。特别是，我们开发了一种新的模型建立方法的灵活的循环区域，基于力偏置的多规范分子动力学（FB-McMD）的隐式溶剂模型，使用广义玻恩近似。该方法可以给出一个精确的蛋白质模型结构，即使是对于柔性环区域，并将其应用于实际通道蛋白的建模。此外，我们还利用我们的新数据库eF-site和HINTdb，利用信息学技术对蛋白质功能及其位点和蛋白质-蛋白质相互作用对进行了识别和预测。为了分析通道蛋白的分子识别，我们开发了一种新的NMR分析方法，其中通过使用交叉饱和转移和残余偶极耦合信号的分子动力学模拟产生复合结构。应用该方法建立了KcsA钾通道与agitoxin-2的复合模型。本文还发展了布朗动力学模拟方法来计算小离子和化合物通过通道蛋白的渗透。

Methods were developed for building tertiary structural models of channel proteins, by combining the inductive homology modeling method and the deductive molecular simulation for low-homologous regions. In particular, we developed a new model building method for flexible loop regions, based on the Force-Biased Multicanonical Molecular Dynamics (FB-McMD) with the implicit solvent model using the generalized Born approximation. This method could give us a precise protein model structure even for the flexible loop regions, and it was applied to modeling of actual channel proteins. In addition, protein functions with their sites and protein-protein interaction pairs were identified and predicted with the informatics technology using our new databases, eF-site and HINTdb, respectively.In order to analyze the molecular recognition of channel proteins, we have developed a new NMR analysis method, where the complexed structure is produced by molecular dynamics simulations using the cross saturation transfer and the residual dipolar coupling signals. This method was applied to build a complexed model between KcsA K^+-channel and agitoxin-2. Brownian dynamics simulation method was also developed for computing permeation of small ions and compounds through a channel protein.