Infection of human cells by the SARS-CoV2 relies on its binding to a specific receptor and subsequent fusion of the viral and host cell membranes. The fusion peptide (FP), a short peptide segment in the spike protein, plays a central role in the initial penetration of the virus into the host cell membrane, followed by the fusion of the two membranes. Here, we use an array of molecular dynamics (MD) simulations taking advantage of the Highly Mobile Membrane Mimetic (HMMM) model, to investigate the interaction of the SARS-CoV2 FP with a lipid bilayer representing mammalian cellular membranes at an atomic level, and to characterize the membrane-bound form of the peptide. Six independent systems were generated by changing the initial positioning and orientation of the FP with respect to the membrane, and each system was simulated in five independent replicas, each for 300 ns. In 73% of the simulations, the FP reaches a stable, membrane-bound configuration where the peptide deeply penetrated into the membrane. Clustering of the results reveals three major membrane binding modes (binding modes 1-3) where binding mode 1 populates over half of the data points. Taking into account the sequence conservation among the viral FPs and the results of mutagenesis studies establishing the role of specific residues in the helical portion of the FP in membrane association, the significant depth of penetration of the whole peptide, and the dense population of the respective cluster, we propose that the most deeply inserted membrane-bound form (binding mode 1) represents more closely the biologically relevant form. Analysis of FP-lipid interactions shows the involvement of specific residues, previously described as the "fusion active core residues", in membrane binding. Taken together, the results shed light on a key step involved in SARS-CoV2 infection with potential implications in designing novel inhibitors.

中文翻译：

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SARS-CoV2融合肽与人细胞膜的结合模式

SARS-CoV2对人细胞的感染依赖于它与特定受体的结合以及随后病毒和宿主细胞膜的融合。融合肽（FP）是刺突蛋白中的短肽段，在病毒最初渗透到宿主细胞膜中，然后融合两个膜中起着核心作用。在这里，我们利用分子动力学（MD）阵列，利用高度可移动膜模拟（HMMM）模型，研究了SARS-CoV2 FP与在原子水平上代表哺乳动物细胞膜的脂质双层的相互作用，以及以表征肽的膜结合形式。通过更改FP相对于膜的初始定位和方向，生成了六个独立的系统，每个系统都模拟为五个独立的副本，每个副本持续300 ns。在73％的模拟中，FP达到稳定的膜结合构型，其中肽深深渗透到膜中。结果的聚类揭示了三种主要的膜结合模式（结合模式1-3），其中结合模式1占据了一半以上的数据点。考虑到病毒FP之间的序列保守性和诱变研究的结果，确定了FP螺旋部分中特定残基在膜缔合中的作用，整个肽的显着渗透深度以及各自的密集种群我们建议最深插入的膜结合形式（结合模式1）更紧密地代表生物学上相关的形式。FP-脂质相互作用的分析显示了膜结合中涉及特定的残基，先前称为“融合活性核心残基”。两者合计，结果阐明了SARS-CoV2感染所涉及的关键步骤，对设计新型抑制剂具有潜在的意义。