高等学校化学学报 ›› 2021, Vol. 42 ›› Issue (8): 2550.doi: 10.7503/cjcu20210106

• 物理化学 • 上一篇    下一篇

基于分子模拟方法预测PIP2在双孔钾通道TREK-1上结合位点的研究

雷晓彤, 金怡卿, 孟烜宇()   

  1. 苏州大学医学部放射医学与防护学院, 定量生物与医学研究中心, 放射医学与辐射防护国家重点实验室, 江苏省高校放射医学协同创新中心, 苏州 215123
  • 收稿日期:2021-02-19 出版日期:2021-08-10 发布日期:2021-08-05
  • 通讯作者: 孟烜宇 E-mail:xymeng@suda.edu.cn
  • 基金资助:
    国家自然科学基金(21503140)

Prediction of the Binding Site of PIP2 in the TREK-1 Channel Based on Molecular Modeling

LEI Xiaotong, JIN Yiqing, MENG Xuanyu()   

  1. School of Radiation Medicine and Protection,Institute of Quantitative Biology and Medicine,State Key Laboratory of Radiation Medicine and Protection,Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions,Soochow University,Suzhou 215123,China
  • Received:2021-02-19 Online:2021-08-10 Published:2021-08-05
  • Contact: MENG Xuanyu E-mail:xymeng@suda.edu.cn
  • Supported by:
    the National Natural Science Foundation of China(21503140)

摘要:

磷脂酰肌醇4,5-二磷酸酯(PIP2)是一类分布在质膜内层的信号磷脂分子, 对钾、 钠和氯等离子通道和转运蛋白等多种跨膜蛋白具有调节作用. TREK-1是一类重要的背景钾通道, 受温度、 机械拉伸及胞内pH等多种因素调节, PIP2在特定浓度范围内可激活TREK-1通道, 在内面向外膜片钳记录TREK-1通道电流中使用PIP2抗结剂(如多聚赖氨酸)可导致TREK-1通道关闭. 利用分子对接和全原子分子动力学模拟探索了PIP2与双孔钾通道TREK-1的相互作用. 分子对接计算结果表明, PIP2在TREK-1通道上有两个可能的结合位点. 进一步的分子动力学模拟和均力势(PMF)计算结果表明, 其中位于螺旋M4和螺旋M1的位点可能是PIP2激活TREK-1的优先结合位点. 模拟展示了PIP2与TREK-1结合的可能构象. PIP2的肌醇头部磷酸根与位于M1和M4上的碱性残基K45, K304和R311形成稳定盐桥; M1螺旋上的一系列疏水残基对稳定PIP2的脂肪长链具有关键作用.

关键词: TREK-1通道, 磷脂酰肌醇4,5-二磷酸酯, 分子对接, 分子动力学模拟, 均力势

Abstract:

Phosphatidylinositol 4,5-bisphosphate(PIP2) is a type of signaling phospholipid molecule distri-buted in the inner layer of the plasma membrane, which has regulatory effects on various transmembrane proteins such as potassium, sodium, chloride ion channels and transporters. TREK-1 is an important background potassium channel, which is regulated by various factors such as temperature, mechanical stretch, intracellular pH, etc. PIP2 activates the TREK-1 channel in a specific concentration range. Treatment of poly-lysine to inhibit the PIP2 in the inside-out patch clamp can cause the TREK-1 channel to close. Molecular docking and all-atom molecular dynamics simulation were used to explore the interaction of PIP2 on the two-pore-domain potassium channel TREK-1. Molecular docking calculations showed that PIP2 has two possible binding sites on the TREK-1 channel to activate the channel. Further use of molecular dynamics simulations and potential of mean force(PMF) calculations showed that the site located between the helix M4 and helix M1 is the preferential binding site for PIP2 to activate TREK-1. The simulation displayed the possible configuration of PIP2 bin-ding to TREK-1. The phosphate groups in inositol head of PIP2 form stable salt bridges with the basic residues K45 located on M1, and K304 and R311 located on M4; K304 and R311 have been verified by mutation experiments, which play an important role in the activation of TREK-1 by PIP2. In addition, a series of hydrophobic residues on the helix M1 play key roles in stabilizing the long fat chains of PIP2.

Key words: TREK-1 channel, Phosphatidylinositol 4, 5-bisphosphate(PIP2), Molecular docking, Molecular dynamics simulation, Potential of mean force(PMF)

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