Binding mode of SARS-CoV-2 fusion peptide to human cellular membrane.
Binding mode of SARS-CoV-2 fusion peptide to human cellular membrane.
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DOI：
10.1016/j.bpj.2021.02.041
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发表时间：
2021-07-20
影响因子：
3.4
通讯作者：
Tajkhorshid E
中科院分区：
文献类型：
--
作者：
Gorgun D;Lihan M;Kapoor K;Tajkhorshid E
严重急性呼吸道综合征冠状病毒2（SARS-CoV 2）感染人类细胞依赖于其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）是刺突蛋白中的一个短肽段，在病毒最初穿透宿主细胞膜，随后两种膜融合中起核心作用。在这里，我们使用一系列的分子动力学模拟，利用高度移动的膜模拟模型，调查的相互作用的SARS-CoV 2 FP与脂质双层代表哺乳动物细胞膜在原子水平和表征的膜结合形式的肽。通过改变FP相对于膜的初始定位和取向生成六个独立的系统，并且每个系统在五个独立的复制品中进行模拟，每个复制品持续300 ns。在73%的模拟中，FP达到稳定的膜结合构型，其中肽深深地渗透到膜中。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，建立膜协会的FP的螺旋部分中的特定残基的作用，整个肽的渗透的显着深度，和各自的集群的密集人口，我们建议，最深插入的膜结合形式（结合模式1）代表更密切的生物相关的形式。FP-脂质相互作用的分析表明，参与特定的残基，以前被描述为“融合活性的核心残基”，在膜结合。总之，这些结果揭示了SARS-CoV 2感染的关键步骤，并对设计新型抑制剂具有潜在意义。
Infection of human cells by the severe acute respiratory syndrome coronavirus 2 (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 simulations that take advantage of the highly mobile membrane mimetic 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, in which the peptide deeply penetrated into the membrane. Clustering of the results reveals three major membrane-binding modes (binding modes 1–3), in which 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.
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56.9
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通讯作者：
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