Assembly of Influenza Hemagglutinin Fusion Peptides in a Phospholipid Bilayer by Coarse-grained Computer Simulations.
Assembly of Influenza Hemagglutinin Fusion Peptides in a Phospholipid Bilayer by Coarse-grained Computer Simulations.
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DOI：
10.3389/fmolb.2015.00066
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发表时间：
2015
影响因子：
5
通讯作者：
Fraternali F
中科院分区：
文献类型：
--
作者：
Collu F;Spiga E;Lorenz CD;Fraternali F
膜融合对于真核细胞功能至关重要，并且对于包膜病毒如流感病毒和人类免疫缺陷病毒的进入至关重要。流感病毒进入宿主细胞由20-23个氨基酸长的序列介导，称为融合肽（FP）。最近，已经提出了融合肽的可能结构（从倒V形α-螺旋结构到α-螺旋发夹结构，或到完整的α-螺旋结构）及其在膜融合起始中的意义。尽管有大量的研究致力于FP的结构，这种肽的作用机制仍然不清楚，已经提出了几种机制，包括诱导局部疾病，促进膜弯曲，和/或改变局部膜组成。近年来，一些研究小组采用原子和/或粗粒度分子动力学（MD）模拟来研究这一问题。在所有以前的工作中，研究了单个FP单体的行为，而在本手稿中，我们使用FP（TFP）的三肽（TP）单体而不是单个FP单体的简化模型，因为每个流感血凝素在生物系统中包含三个FP分子。在这份手稿中，我们报告的结果，旨在了解的融合特性和集体行为的FP肽的这些三聚体上的1-棕榈酰-2-油酰-sn-甘油-3-磷酸胆碱模型膜。在这里，我们展示了TFP单体如何在膜的存在下自组装成不同大小的低聚物。我们测量这些TFP低聚物的存在所造成的磷脂膜的结构的扰动。我们的工作（i）显示了TFP在膜存在下的自组装如何引起膜的不可忽略的变形，（ii）可能是一个有用的起点，以刺激讨论和进一步的工作，以融合孔的形成为目标。
Membrane fusion is critical to eukaryotic cellular function and crucial to the entry of enveloped viruses such as influenza and human immunodeficiency virus. Influenza viral entry in the host cell is mediated by a 20–23 amino acid long sequence, called the fusion peptide (FP). Recently, possible structures for the fusion peptide (ranging from an inverted V shaped α-helical structure to an α-helical hairpin, or to a complete α-helix) and their implication in the membrane fusion initiation have been proposed. Despite the large number of studies devoted to the structure of the FP, the mechanism of action of this peptide remains unclear with several mechanisms having been suggested, including the induction of local disorder, promoting membrane curvature, and/or altering local membrane composition. In recent years, several research groups have employed atomistic and/or coarse-grained molecular dynamics (MD) simulations to investigate the matter. In all previous works, the behavior of a single FP monomer was studied, while in this manuscript, we use a simplified model of a tripeptide (TP) monomer of FP (TFP) instead of a single FP monomer because each Influenza Hemagglutinin contains three FP molecules in the biological system. In this manuscript we report findings targeted at understanding the fusogenic properties and the collective behavior of these trimers of FP peptides on a 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine model membrane. Here we show how the TFP monomers self-assemble into differently sized oligomers in the presence of the membrane. We measure the perturbation to the structure of the phospholipid membrane caused by the presence of these TFP oligomers. Our work (i) shows how self-assembly of TFP in the presence of the membrane induces non negligible deformation to the membrane and (ii) could be a useful starting point to stimulate discussion and further work targeted to fusion pore formation.