Understanding how membrane composition influences the dynamics and function of transmembrane proteins is crucial for the comprehensive elucidation of cellular signaling mechanisms and the development of targeted therapeutics. In this study, we employed all-atom molecular dynamics simulations to investigate the impact of different membrane compositions on the conformational dynamics of the NKG2A/CD94/HLA-E immune receptor complex, a key negative regulator of natural killer cell cytotoxic activity. Our results reveal significant variations in the behavior of the immune complex structure across five different membrane compositions, which include POPC, POPA, DPPC, and DLPC phospholipids, and a mixed POPC/cholesterol system. These variations are particularly evident in the intracellular domain of NKG2A, manifested as changes in mobility, tyrosine exposure, and interdomain communication. Additionally, we found that a large concentration of negative charge at the surface of the POPA-based membrane greatly increased the number of contacts with lipid molecules and significantly decreased the exposure of intracellular NKG2A ITIM regions to water molecules, thus likely halting the signal transduction process. Furthermore, the DPPC model with a membrane possessing a high transition temperature in a gel-like state became curved, affecting the exposure of one ITIM region. The decreased membrane thickness in the DPLC model caused a significant transmembrane domain tilt, altering the linker protrusion angle and potentially disrupting the hydrogen bonding network in the extracellular domain. Overall, our findings highlight the importance of considering membrane composition in the analysis of transmembrane protein dynamics and in the exploration of novel strategies for the external modulation of their signaling pathways.

中文翻译：

---

全原子模拟揭示了膜组成对 NKG2A/CD94/HLA-E 免疫受体复合物信号传导的影响。


了解膜组成如何影响跨膜蛋白的动力学和功能对于全面阐明细胞信号转导机制和开发靶向治疗药物至关重要。在这项研究中，我们采用全原子分子动力学模拟来研究不同膜组成对 NKG2A/CD94/HLA-E 免疫受体复合物构象动力学的影响，NKG2A/CD94/HLA-E 免疫受体复合物是自然杀伤细胞细胞毒活性的关键负调节因子。我们的结果揭示了免疫复合物结构在五种不同膜组成中的行为存在显着变化，其中包括 POPC、POPA、DPPC 和 DLPC 磷脂，以及混合的 POPC/胆固醇系统。这些变化在 NKG2A 的细胞内结构域中尤为明显，表现为迁移率、酪氨酸暴露和结构域间通讯的变化。此外，我们发现基于 POPA 的膜表面的高浓度负电荷大大增加了与脂质分子的接触次数，并显着减少了细胞内 NKG2A ITIM 区域对水分子的暴露，因此可能停止信号转导过程。此外，在凝胶状状态下具有高转变温度的膜的 DPPC 模型变得弯曲，影响了一个 ITIM 区域的曝光。DPLC 模型中膜厚度的减少导致显着的跨膜结构域倾斜，改变接头突出角度，并可能破坏细胞外结构域中的氢键网络。 总体而言，我们的研究结果强调了在分析跨膜蛋白动力学和探索其信号通路外部调节的新策略中考虑膜组成的重要性。