Shen Hujun, Wu Qingqing, Chen Ling
Guizhou Provincial Key Laboratory of Computational Nano-Material Science, Guizhou Education University, Guiyang 550018, China.
Phys Chem Chem Phys. 2025 Aug 13;27(32):16962-16971. doi: 10.1039/d5cp01030f.
Ether phospholipids are believed to play crucial roles in various biological functions. Previous research has indicated that substituting ester linkages with ether linkages in lipid head groups leads to a significant reduction in the membrane dipole potential. In this study, we constructed hybrid lipid bilayer systems that included both ether-linked (DMPCE) and ester-linked (DMPC) phospholipids. Our goal was to understand how the ether lipid content in the hybrid lipid bilayers affects the interaction between the SARS-CoV-2 fusion peptide (FP) and cellular membranes. To achieve this, we systematically adjusted the stoichiometric ratios to create four hybrid membrane models: two were ester-predominant and another two were ether-enriched. Our molecular dynamics (MD) simulations revealed several intriguing findings. First, it is surprising that at low-to-moderate DMPCE concentrations, the presence of ether phospholipids caused only minor changes in the overall structural properties of the hybrid bilayer membranes, including the membrane dipole potential. However, at a higher level of ether lipid, there is a significant impact on the structural properties and the dipole potential of the lipid bilayer membrane. This composition-dependent behavior implies that while the structural integrity of ester lipid bilayers remains relatively unaffected by low-to-moderate levels of ether lipid incorporation, exceeding a critical concentration threshold would result in observable structural changes in the lipid bilayer. Furthermore, the content of ether phospholipids had a significant impact on the conformation of the SARS-CoV-2 FP and its binding to hybrid membranes. Our current results indicate that the biophysical effects of partial ether lipid substitution follow a non-linear response to composition. This refined understanding advances earlier models by demonstrating that hybrid bilayers maintain compositional resilience within specific operational ranges.
醚磷脂被认为在各种生物学功能中发挥着关键作用。先前的研究表明，脂质头部基团中的酯键被醚键取代会导致膜偶极电位显著降低。在本研究中，我们构建了包含醚连接的（DMPCE）和酯连接的（DMPC）磷脂的混合脂质双层系统。我们的目标是了解混合脂质双层中醚脂质含量如何影响严重急性呼吸综合征冠状病毒2（SARS-CoV-2）融合肽（FP）与细胞膜之间的相互作用。为了实现这一目标，我们系统地调整化学计量比以创建四个混合膜模型：两个以酯为主，另外两个富含醚。我们的分子动力学（MD）模拟揭示了几个有趣的发现。首先，令人惊讶的是，在低至中等DMPCE浓度下，醚磷脂的存在仅对混合双层膜的整体结构性质产生微小变化，包括膜偶极电位。然而，在较高水平的醚脂质情况下，对脂质双层膜的结构性质和偶极电位有显著影响。这种组成依赖性行为意味着，虽然酯脂质双层的结构完整性相对不受低至中等水平醚脂质掺入的影响，但超过临界浓度阈值会导致脂质双层中可观察到的结构变化。此外，醚磷脂的含量对SARS-CoV-2 FP的构象及其与混合膜的结合有显著影响。我们目前的结果表明，部分醚脂质取代的生物物理效应遵循对组成的非线性响应。这种更精确的理解通过证明混合双层在特定操作范围内保持组成弹性，推进了早期模型。
