流感病毒血凝素膜锚构象转变背后的分子机制,The Journal of Physical Chemistry B

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流感病毒血凝素膜锚构象转变背后的分子机制
The Journal of Physical Chemistry B ( IF 2.8 ) Pub Date : 2023-10-25 , DOI: 10.1021/acs.jpcb.3c05257
Michal Michalski ₁ , Piotr Setny ₁

Affiliation

膜融合是有包膜病毒利用其进入宿主细胞的基本过程。就流感病毒而言，三聚体病毒血凝素蛋白（HA）促进融合。到目前为止，主要焦点集中在其 N 端融合肽上，它直接负责融合启动。越来越多的证据也表明 HA C 末端结构域具有重要的功能作用，但人们对此仍不完全了解。我们的计算研究旨在阐明包含跨膜结构域 (TMD) 和细胞质尾 (CT) 的 HA C 末端区域内结构和功能的相互依赖性。我们特别感兴趣的是 TMD 响应病毒膜中不同胆固醇浓度而发生的构象变化，以及 CT 的存在对其的调节。使用基于原子分子动力学模拟的自由能计算，我们表征了不同条件下直亚稳态 TMD 构型和倾斜亚稳态 TMD 构型之间的转变。我们发现 CT 的存在对于实现稳定、高度倾斜的 TMD 配置至关重要。正如我们所证明的，HA 膜锚的这种配置可能支持其胞外域的倾斜运动，这需要在膜融合过程中执行。这一发现凸显了迄今为止相对被忽视的 CT 区域的功能作用。

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Molecular Mechanisms behind Conformational Transitions of the Influenza Virus Hemagglutinin Membrane Anchor

Membrane fusion is a fundamental process that is exploited by enveloped viruses to enter host cells. In the case of the influenza virus, fusion is facilitated by the trimeric viral hemagglutinin protein (HA). So far, major focus has been put on its N-terminal fusion peptides, which are directly responsible for fusion initiation. A growing body of evidence points also to a significant functional role of the HA C-terminal domain, which however remains incompletely understood. Our computational study aimed to elucidate the structural and functional interdependencies within the HA C-terminal region encompassing the transmembrane domain (TMD) and the cytoplasmic tail (CT). In particular, we were interested in the conformational shift of the TMD in response to varying cholesterol concentration in the viral membrane and in its modulation by the presence of CT. Using free-energy calculations based on atomistic molecular dynamics simulations, we characterized transitions between straight and tilted metastable TMD configurations under varying conditions. We found that the presence of CT is essential for achieving a stable, highly tilted TMD configuration. As we demonstrate, such a configuration of HA membrane anchor likely supports the tilting motion of its ectodomain, which needs to be executed during membrane fusion. This finding highlights the functional role of, so far, the relatively overlooked CT region.

更新日期：2023-10-25

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