弱电相互作用下钾离子跨膜输运机制的研究

In long-term, sustained support from the National Natural Science Foundation, our group has been engaged in revealing the molecular mechanism of ion transmembrane transport and convinced that there are two type of interactions which modulate the conformation of ion channels and play key roles in ion transmembrane transport. These interactions are weak interaction between the membrane phospholipid PIP2 and specific amino acids and electrostatic interaction between the permeable ions and channels, collectively known as the weak-elctric interactions. In the present work, we will combine the experiments of molecular biology with theoretical analysis and focus on understanding of the molecular mechanism of how the weak-elctric interactions couple together and modulate the gating of ion channels. We strive for a more in-depth pathological understanding of ion channel diseases and promote the progress of targeted drug design and treatment. The present study will increase the combination of life sciences and physics, especially the combination of biological experiments and theoretical analysis.

在国家自然科学基金持续支持下，课题组逐步认识到钾离子跨膜输运机制的的核心问题与两种相互作用有关：即膜磷脂PIP2与通道内特定氨基酸之间的弱相互作用和通道内外的通透离子对通道的静电相互作用。这两种相互作用可简称为弱电相互作用。 本项目将围绕对弱电相互作用下钾离子跨膜输运机制进行更为深入的探讨，开展分子生物学实验与理论分析并重的研究，重点讨论两种基本相互作用协同、耦合的离子跨膜输运的分子机制。力求对这一复杂生命过程及其物理问题有更加深入的了解，并为随之开展的钾离子通道相关疾病靶向药物设计与合成工作提供基础理论支撑，促进生命科学与物理学，特别是生物学实验与理论分析的有机结合。

内向整流钾离子（Kir）通道广泛分布于心肌细胞，神经元细胞，血细胞等各种细胞上。Kir通道参与了众多的生理过程，例如维持细胞的静息膜电位，控制细胞的兴奋性，调控心率、血管张力等，这些生理功能都依赖于Kir通道的门在开放态和关闭态之间的构象转变，即门控过程。本研究以Kir通道为研究对象，采用同源模建的方法构建了关闭态和开放态的三维结构模型、将分子动力学模拟和靶向分子动力学模拟相结合，研究Kir2.1了通道门控过程，实现了Kir2.1通道门控对应的构象变化过程。并阐明了胞内外离子形成的静电相互作用调控Kir通道钾离子跨膜通透的分子机制，并进一步阐释了Kir通道的内向整流与门控变构相互耦合作用机制。本研究还涉及到了二价阳离子-钙离子调控钙调蛋白变构的分子机制和钙离子诱导BK通道构象变化过程中，阐释了相互作用力产生、远程传递路径的分子机制，甄别出影响门控变构的关键氨基酸与结构域。最后，我们筛选出几种调控Kir2，TMEM16A，Kv10.1通道天然产物小分子，并结合项目主要研究内容阐明了其作用机理。