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Molecular dynamics study of membrane permeabilization by wild-type and mutant lytic peptides from the non-enveloped Flock House virus.
Biochimica et Biophysica Acta (BBA) - Biomembranes ( IF 3.4 ) Pub Date : 2019-10-31 , DOI: 10.1016/j.bbamem.2019.183102 Shivangi Nangia 1 , Kevin J Boyd 1 , Eric R May 1
Biochimica et Biophysica Acta (BBA) - Biomembranes ( IF 3.4 ) Pub Date : 2019-10-31 , DOI: 10.1016/j.bbamem.2019.183102 Shivangi Nangia 1 , Kevin J Boyd 1 , Eric R May 1
Affiliation
Flock House virus (FHV) serves as a model system for understanding infection mechanisms utilized by non-enveloped viruses to transport across cellular membranes. During the infection cycle of FHV, a fundamental stage involves disruption of the endosomal membrane by membrane active peptides, following externalization of the peptides from the capsid interior. The FHV lytic agents are the 44 C-terminal amino acids residues of the capsid protein, which are auto-catalytically cleaved during the capsid maturation process. The cleaved peptides are termed γ peptides. In this study, we perform multi-scale molecular dynamics simulations including 40 μs all-atom molecular dynamics simulations to study the behavior of pre-inserted transmembrane lytic peptides at a high concentration in a neutral membrane. We study the dynamical organization among peptides to form oligomeric bundles in four systems including the wild-type γ peptide and three mutant forms; namely, a truncation mutant in which the 23 C-terminal residues are deleted (γ1), a construct where the 8 C-terminal residues of γ are fused to γ1 (Δ385-399 γ) and a single-point mutant (F402A γ), all of which have been experimentally shown to drastically affect infectivity and lytic activity compared to the wild-type γ. Our results shed light on the actions of varied forms of the FHV lytic peptide including membrane insertion, trans-membrane stability, peptide oligomerization, water permeation activity and dynamic pore formation. Findings from this study provide detailed structural information and rationale for the differences in lytic activity among variants of FHV γ.
中文翻译:
非包膜羊群病毒的野生型和突变型裂解肽对膜通透性的分子动力学研究。
鸡群病毒(FHV)作为模型系统,用于了解非包膜病毒用于跨细胞膜运输的感染机制。在FHV的感染周期中,一个基本阶段包括在从衣壳内部将肽外化之后,膜活性肽破坏内体膜。FHV裂解剂是衣壳蛋白的44个C末端氨基酸残基,可在衣壳成熟过程中自动催化裂解。切割的肽称为γ肽。在这项研究中,我们进行了包括40μs全原子分子动力学模拟在内的多尺度分子动力学模拟,以研究在中性膜中高浓度预插入的跨膜溶解肽的行为。我们研究了肽之间的动态组织,以在包括野生型γ肽和三种突变体形式的四个系统中形成寡聚束。即,缺失了23个C末端残基的截短突变体(γ1),将γ的8个C末端残基与γ1融合的构建体(Δ385-399γ)和单点突变体(F402Aγ) ,与野生型γ相比,所有这些均已通过实验证明对感染性和裂解活性有极大影响。我们的结果揭示了FHV裂解肽的各种形式的作用,包括膜插入,跨膜稳定性,肽寡聚,水渗透活性和动态孔形成。这项研究的发现为FHVγ变体之间的裂解活性差异提供了详细的结构信息和原理。
更新日期:2019-11-01
中文翻译:
非包膜羊群病毒的野生型和突变型裂解肽对膜通透性的分子动力学研究。
鸡群病毒(FHV)作为模型系统,用于了解非包膜病毒用于跨细胞膜运输的感染机制。在FHV的感染周期中,一个基本阶段包括在从衣壳内部将肽外化之后,膜活性肽破坏内体膜。FHV裂解剂是衣壳蛋白的44个C末端氨基酸残基,可在衣壳成熟过程中自动催化裂解。切割的肽称为γ肽。在这项研究中,我们进行了包括40μs全原子分子动力学模拟在内的多尺度分子动力学模拟,以研究在中性膜中高浓度预插入的跨膜溶解肽的行为。我们研究了肽之间的动态组织,以在包括野生型γ肽和三种突变体形式的四个系统中形成寡聚束。即,缺失了23个C末端残基的截短突变体(γ1),将γ的8个C末端残基与γ1融合的构建体(Δ385-399γ)和单点突变体(F402Aγ) ,与野生型γ相比,所有这些均已通过实验证明对感染性和裂解活性有极大影响。我们的结果揭示了FHV裂解肽的各种形式的作用,包括膜插入,跨膜稳定性,肽寡聚,水渗透活性和动态孔形成。这项研究的发现为FHVγ变体之间的裂解活性差异提供了详细的结构信息和原理。