通过分子动力学模拟,剖析TLR4/MD2与Neoseptin-3反体的奇拉性识别
Cong Zhang1,2, Siru Wu1,2, Mingqi Li1,2
1Laboratory of Chemical Biology, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, China. yibo.wang@ciac.ac.cn.
Physical chemistry chemical physics : PCCP
|March 1, 2024
概括
收费类受体4 (TLR4) 选择性地结合L-Neo-3反体,激活免疫信号传递. 计算模拟显示,L-Neo-3顺序进入TLR4/MD2复合体,稳定其结构,而D-Neo-3由于硬质障碍而被排斥.
科学领域:
- 免疫学和分子生物学
- 计算化学和结构生物学
背景情况:
- 收费类受体4 (TLR4) 是一个关键的先天性免疫受体,参与病原体识别和免疫反应.
- 尼奥-3 (Neo-3) 是一种性小分子,作为小鼠TLR4/MD2的激动剂,只有L-enantiomer (L-Neo-3) 激活受体.
- 对于TLR4对Neo-3的对抗选择性识别的确切机制尚不清楚.
研究的目的:
- 阐明了TLR4/MD2对L-Neo-3和D-Neo-3进行反选择性识别的原子层次机制.
- 通过计算模拟,研究TLR4/MD2复合体内的Neo-3反体的结合动力学和稳定效应.
主要方法:
- 在基分子动力学模拟中,使用模拟Neo-3反体与TLR4/MD2复合物的相互作用.
- 模拟包括标准分子动力学和采样技术,以分析结合能和构造变化.
- 分析的重点是Neo-3二元的稳定性,它们进入MD2腔,以及它们对TLR4/MD2二元化的影响.
主要成果:
- 观察到两个L-Neo-3分子在MD2腔内稳定结合为二聚体,稳定了 (TLR4/MD2) 2复合体.
- D-Neo-3分子经历了显著的静电排斥,阻止了稳定的二次体形成和在 (TLR4/MD2) 2复合体内的相互作用.
- 雨采样表明L-Neo-3在MD2的序列进入,第二个分子表现出较低的结合能量,这表明结合容易.
结论:
- 由于L-Neo-3和D-Neo-3与结合口袋的明显相互作用,TLR4/MD2表现出对Neo-3的酶选择性结合.
- L-Neo-3分子对MD2的顺序性,合作性结合对于稳定活性 (TLR4/MD2) 2复合体和启动下游信号传输至关重要.
- 这项研究提供了详细的机械洞察力,以在分子层面上对TLR4激动剂的奇拉性识别.
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