Lipid tail protrusion in simulations predicts fusogenic activity of influenza fusion peptide mutants and conformational models.
Lipid tail protrusion in simulations predicts fusogenic activity of influenza fusion peptide mutants and conformational models.
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DOI：
10.1371/journal.pcbi.1002950
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发表时间：
2013
影响因子：
4.3
通讯作者：
Kasson PM
中科院分区：
文献类型：
--
作者：
Larsson P;Kasson PM
来自流感血凝素的融合肽作用于膜以促进膜融合，但它们这样做的机制仍然未知。最近的理论工作表明，突出的脂质尾部的接触可能是膜融合的过渡态的一个重要特征。如果是这样，那么预期流感融合肽促进尾部突出与相应全长血凝素在融合测定中驱动脂质混合的能力成比例。我们进行了分子动力学模拟的流感融合肽的脂质双层，比较X-31流感病毒株对一系列的N-末端突变体。如所假设的，脂质尾部突出的概率与由每个突变体诱导的脂质混合速率良好相关。这支持了尾部突出对融合过渡态的重要性的结论。此外，这表明尾部突出可以用于检查融合肽如何与膜相互作用以促进融合。膜中天然流感融合肽结构的先前模型包括扭结螺旋、直螺旋和螺旋发夹。我们的模拟访问这些构象中的每一个。因此，每个之间的自由能差异可能足够低，使得膜环境和肽构建体的特性可能足以调节它们之间的平衡。然而，在我们的模拟中，扭结的螺旋比其他两种结构更强烈地促进脂质尾突出。因此，我们预测扭结螺旋是这三种构象中最易融合的。膜融合是细胞功能和包膜病毒感染的一个重要过程。流感是研究融合的一个特别有用的模型系统，因为融合反应是由一个单一的蛋白质，血凝素。此外，已经鉴定出血凝素的膜插入部分的突变不会显著改变蛋白质的其余部分，但可以在一半时阻止融合或完全阻断融合。至少对于流感病毒来说，似乎膜插入的血凝素肽在促进融合中起着关键作用，可能是通过增加脂质双层的局部紊乱。然而，我们缺乏一个机制的理解，足以预测的融合肽突变体的活性，从他们的序列。在这里，我们已经使用脂质尾突出作为一种方法来衡量多少融合肽紊乱其周围的双层，我们看到了很强的关系之间的脂质尾突出和融合肽突变体的能力，以促进膜之间的脂质混合。我们的模拟还预测，当肽采用扭结螺旋结构时，这种脂质尾部突出比当它们是直的或发夹状时更常见。因此，我们假设，虽然所有三种类型的结构可能进行构象交换，扭结的螺旋结构是最积极的促进融合。
Fusion peptides from influenza hemagglutinin act on membranes to promote membrane fusion, but the mechanism by which they do so remains unknown. Recent theoretical work has suggested that contact of protruding lipid tails may be an important feature of the transition state for membrane fusion. If this is so, then influenza fusion peptides would be expected to promote tail protrusion in proportion to the ability of the corresponding full-length hemagglutinin to drive lipid mixing in fusion assays. We have performed molecular dynamics simulations of influenza fusion peptides in lipid bilayers, comparing the X-31 influenza strain against a series of N-terminal mutants. As hypothesized, the probability of lipid tail protrusion correlates well with the lipid mixing rate induced by each mutant. This supports the conclusion that tail protrusion is important to the transition state for fusion. Furthermore, it suggests that tail protrusion can be used to examine how fusion peptides might interact with membranes to promote fusion. Previous models for native influenza fusion peptide structure in membranes include a kinked helix, a straight helix, and a helical hairpin. Our simulations visit each of these conformations. Thus, the free energy differences between each are likely low enough that specifics of the membrane environment and peptide construct may be sufficient to modulate the equilibrium between them. However, the kinked helix promotes lipid tail protrusion in our simulations much more strongly than the other two structures. We therefore predict that the kinked helix is the most fusogenic of these three conformations. Membrane fusion is a common process critical to both cellular function and infection by enveloped viruses. Influenza is a particularly useful model system for studying fusion because the fusion reaction is accomplished by a single protein, hemagglutinin. Furthermore, mutations to the membrane-inserted portion of hemagglutinin have been identified that do not detectably alter the rest of the protein but can either arrest fusion halfway or block it entirely. For influenza at least, it seems that the membrane-inserted hemagglutinin peptide plays a critical role in promoting fusion, perhaps by increasing the local disorder of lipid bilayers. However, we lack a mechanistic understanding sufficient to predict the activity of fusion peptide mutants from their sequence. Here, we have used lipid tail protrusion as a way to measure how much fusion peptides disorder their surrounding bilayer; we see a strong relationship between lipid tail protrusion and the ability of fusion peptide mutants to promote lipid mixing between membranes. Our simulations also predict that this lipid tail protrusion is much more common when the peptides adopt a kinked helix structure than when they are straight or hairpin-like. We therefore hypothesize that, while all three types of structure likely undergo conformational exchange, the kinked helix structure is most active in promoting fusion.
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