Laboratory of Computational Biology, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
Section on Integrative Biophysics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
Nat Commun. 2022 Dec 5;13(1):7336. doi: 10.1038/s41467-022-34576-z.
To infect, enveloped viruses employ spike protein, spearheaded by its amphipathic fusion peptide (FP), that upon activation extends out from the viral surface to embed into the target cellular membrane. Here we report that synthesized influenza virus FPs are membrane active, generating pores in giant unilamellar vesicles (GUV), and thus potentially explain both influenza virus' hemolytic activity and the liposome poration seen in cryo-electron tomography. Experimentally, FPs are heterogeneously distributed on the GUV at the time of poration. Consistent with this heterogeneous distribution, molecular dynamics (MD) simulations of asymmetric bilayers with different numbers of FPs in one leaflet show FP aggregation. At the center of FP aggregates, a profound change in the membrane structure results in thinning, higher water permeability, and curvature. Ultimately, a hybrid bilayer nanodomain forms with one lipidic leaflet and one peptidic leaflet. Membrane elastic theory predicts a reduced barrier to water pore formation when even a dimer of FPs thins the membrane as above, and the FPs of that dimer tilt, to continue the leaflet bending initiated by the hydrophobic mismatch between the FP dimer and the surrounding lipid.
为了感染，包膜病毒采用刺突蛋白，由其两亲融合肽（FP）带头，一旦被激活，它就会从病毒表面伸出，嵌入靶细胞膜。在这里，我们报告说合成的流感病毒 FP 是膜活性的，在巨大的单分子层囊泡（GUV）中产生孔，因此可能解释了流感病毒的溶血活性和冷冻电子断层扫描中观察到的脂质体穿孔。实验上，在穿孔时，FP 在 GUV 上呈异质分布。与这种异质分布一致，在一个叶状层中具有不同数量 FP 的不对称双层的分子动力学（MD）模拟显示 FP 聚集。在 FP 聚集体的中心，膜结构发生深刻变化，导致变薄、更高的水渗透性和曲率。最终，形成具有一个脂双层和一个肽层的混合双层纳米域。膜弹性理论预测，当 FP 二聚体将膜变薄时，即使形成水孔形成的屏障也会降低，并且该二聚体的 FP 倾斜，以继续由 FP 二聚体与周围脂质之间的疏水性失配引发的叶状层弯曲。
