Centre of New Technologies, University of Warsaw, Warsaw, Poland.
PLoS Comput Biol. 2023 May 26;19(5):e1011174. doi: 10.1371/journal.pcbi.1011174. eCollection 2023 May.
The entry of influenza virus into the host cell requires fusion of its lipid envelope with the host membrane. It is catalysed by viral hemagglutinin protein, whose fragments called fusion peptides become inserted into the target bilayer and initiate its merging with the viral membrane. Isolated fusion peptides are already capable of inducing lipid mixing between liposomes. Years of studies indicate that upon membrane binding they form bend helical structure whose degree of opening fluctuates between tightly closed hairpin and an extended boomerang. The actual way in which they initiate fusion remains elusive. In this work we employ atomistic simulations of wild type and fusion inactive W14A mutant of influenza fusion peptides confined between two closely apposed lipid bilayers. We characterise peptide induced membrane perturbation and determine the potential of mean force for the formation of the first fusion intermediate, an interbilayer lipid bridge called stalk. Our results demonstrate two routes through which the peptides can lower free energy barrier towards fusion. The first one assumes peptides capability to adopt transmembrane configuration which subsequently promotes the creation of a stalk-hole complex. The second involves surface bound peptide configuration and proceeds owing to its ability to stabilise stalk by fitting into the region of extreme negative membrane curvature resulting from its formation. In both cases, the active peptide conformation corresponds to tight helical hairpin, whereas extended boomerang geometry appears to be unable to provide favourable thermodynamic effect. The latter observation offers plausible explanation for long known inactivity of boomerang-stabilising W14A mutation.
流感病毒进入宿主细胞需要其脂质包膜与宿主膜融合。它是由病毒血凝素蛋白催化的，其片段称为融合肽，插入靶双层并启动与病毒膜的融合。分离的融合肽已经能够诱导脂质体之间的脂质混合。多年的研究表明，在与膜结合后，它们形成弯曲的螺旋结构，其开口程度在紧密关闭的发夹和扩展的回飞棒之间波动。它们启动融合的实际方式仍然难以捉摸。在这项工作中，我们使用了原子模拟方法，研究了流感融合肽的野生型和融合失活的 W14A 突变体在两个紧密相邻的脂质双层之间的限制。我们描述了肽诱导的膜扰动，并确定了形成第一个融合中间物（称为柄的双层间脂质桥）的平均力势能。我们的结果表明，肽可以通过两种途径降低融合的自由能障碍。第一种假设是肽能够采用跨膜构象，随后促进柄孔复合物的形成。第二种方法涉及表面结合的肽构象，并且由于其能够通过适应其形成导致的极端负膜曲率区域来稳定柄，因此可以进行。在这两种情况下，活性肽构象都对应于紧密的螺旋发夹，而扩展的回飞棒几何形状似乎无法提供有利的热力学效应。后一种观察结果为长期以来已知的回飞棒稳定的 W14A 突变的不活性提供了合理的解释。
