变构调节是ABC转运蛋白发挥生物学功能的基础，因其与肿瘤多药耐药等重要生理过程密切相关，所以对其变构机制的研究引起了广泛关注。项目基于多尺度分子动力学模拟、弹性网络和复杂网络模型，建立和发展有效的分析方法，针对代表性ABC转运体系研究其变构机制。包括：利用多尺度分子动力学方法，考虑膜环境及胆固醇，研究体系各部分对底物结合的响应和其间的耦合动力学，揭示响应差异背后的微观机制。构建考虑氨基酸序列和膜环境的弹性网络模型，研究底物引起的局部结构的扰动如何导致NBD大幅度变构；发展显含考虑底物和具体变构的基于热力学循环的方法，识别体系变构关键残基；建立迭代使用弹性网络模型和多尺度分子动力学的方法，模拟变构路径。搭建由保守残基构成的加权网络，权重体现残基间动力学相关性，识别变构关键残基及信号传递通路。探讨导致体系变构异同的结构和动力学微观机制，加深对ABC转运蛋白功能性变构机理的理解。

Allosteric modulation plays a basic role for the function exertion of ABC transporters. Investigations on the allosteric mechanism have aroused wide concern due to their close relation to multidrug resistance and some other important physiological processes. The aim of this project is to develop effective theoritical methods, based on the multiscale molecular dynamics simulations，elastic network model and complex network model, to study the allosteric mechanisms for the representative ABC transporter systems. The following subjects will be studied. Using multiscale molecular dynamics simulations with the membrane environment and cholesterol considered, we will study the response process of different parts of the ABC transporter to the allosteric signal, and allosteric coupling between them and reveal the microscopic mechanisms behind the response differences.Besides that,We will construct the elastic network model with amino acid sequence and membrane enviroment considered to investigate how the large-scale allosteric motion of NBD is triggered by the perturbation of substrates on the local region in ABC transporters. Meanwhile, a method based on the thermodynamical cycle will be proposed for identifying the key residues involved in ABC transporter allostery, in which substrates and detailed structural changes are explicitly considered in the method. Moreover, we will construct the iteration method of elastic network model and mutiscale molecular dynamics simulations, to simulate the allosteric pathway. In addition, a weighted residue network will be built with conserved residues as nodes and dynamical cross-correlations between residues as weights for analyzing and identifying key residues and allosteric signal transduction pathways. Based on these, we will explore the correlations between the allosteric movement and the system's topology and inherent movement patterns. These above intestigations are helpful for our understanding the allosteric mechanism of ABC transporters.