基于多尺度分子动力学模拟和高精度可极化力场研究PIP2对TRP通道调控的微观分子机理

Membrane phosphatidylinositol-4,5-bisphosphate (PIP2) is critical for regulating the function of transient receptor potential (TRP) ion channels. However, the molecular mechanism of this process is still unknown. The available of the structural information of TRP channels determined by electron cryo-microscopy provide us the opportunity to study the underling mechanism at a microscopic level, but the static structure of TRP channels could not bring us much insight into the relationship between its function and dynamic motions. Computational biology has become a powerful tool to compensate for the experimental limitation by bridging the protein dynamics and its function. In the proposal, we intend to establish the multi-scale molecular dynamic simulation protocol to investigate the dynamic behaviors of TRP channel regulated by PIP2. The next generation polarizable force field could also be utilized to accurately study the molecular mechanism at atomic level. Thus, our investigation would build a strong theoretical basis in understanding the mechanism of TRP channel activation and offer a highly efficient methodology for TRP targeted drug discovery.

PIP2对TRP通道功能的调控起到了至关重要的作用。然而，其微观分子机理至今仍不清晰。得益于TRP通道高分辨率冷冻电镜结构的解析（3.4Å），使我们可以从微观水平对其调控机理进行研究。但是，静态的结构信息难以建立起TRP通道动态结构与功能之间的联系，计算生物学的应用弥补了实验在时空尺度和动态学研究上的不足。本项目中，针对TRP通道冷冻电镜结构分辨率粗、尺度大的特点，我们拟建立多尺度的分子动力学模拟方案，并通过高精度可极化力场研究PIP2对TRP通道调控的微观分子机理，为理解TRP通道的活化机理提供强有力的理论支撑和并为以TRP通道为靶点的药物研发提供高效的研究工具。

瞬时受体电位离子通道蛋白是存在于细胞膜或胞内细胞器膜上的一类非选择性阳离子通道超家族完整膜蛋白，这一家族的通道存在于整个动物界，并广泛分布于包括人类在内的哺乳动物细胞中。目前已有诸多生理、生化实验明 PIP2 与 TRP 通道 CTD 结构域 C 末端的结合对其离子通透性的调控起着至关重要的作用，然而其调节机理仍不清晰。本项目中，我们通过多尺度、高通量的分子动力学模拟深入研究了PIP2与TRP通道相互作用及调控机理。同时，我们发展了基于软硬件结合加速的增强采样IaMD算法，为高精度分子模拟方法针对重要膜蛋白体系动态结构与功能之间关系的微观分子机理研究及复杂生物体系的高精度理论模拟研究提供理论支撑和有效工具.