Victor Bruno L, Lousa Diana, Antunes Jorge M, Soares Cláudio M
ITQB, Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, Av. da República, 2780-157 Oeiras, Portugal.
J Chem Inf Model. 2015 Apr 27;55(4):795-805. doi: 10.1021/ci500756v. Epub 2015 Apr 13.
Influenza virus is one of the most devastating human pathogens. In order to infect host cells, this virus fuses its membrane with the host membrane in a process mediated by the glycoprotein hemagglutinin. During fusion, the N-terminal region of hemagglutinin, which is known as the fusion peptide (FP), inserts into the host membrane, promoting lipid mixing between the viral and host membranes. Therefore, this peptide plays a key role in the fusion process, but the exact mechanism by which it promotes lipid mixing is still unclear. To shed light into this matter, we performed molecular dynamics (MD) simulations of the influenza FP in different environments (water, dodecylphosphocholine (DPC) micelles, and a dimyristoylphosphatidylcholine (DMPC) membrane). While in pure water the peptide lost its initial secondary structure, in simulations performed in the presence of DPC micelles it remained stable, in agreement with previous experimental observations. In simulations performed in the presence of a preassembled DMPC bilayer, the peptide became unstructured and was unable to insert into the membrane as a result of technical limitations of the method used. To overcome this problem, we used a self-assembly strategy, assembling the membrane together with the peptide. These simulations revealed that the peptide can adopt a membrane-spanning conformation, which had not been predicted by previous MD simulation studies. The peptide insertion had a strong effect on the membrane, lowering the bilayer thickness, disordering nearby lipids, and promoting lipid tail protrusion. These results contribute to a better understanding of the role of the FP in the fusion process.
流感病毒是最具破坏力的人类病原体之一。为了感染宿主细胞，这种病毒通过糖蛋白血凝素介导的过程将其膜与宿主膜融合。在融合过程中，血凝素的N端区域，即融合肽（FP），插入宿主膜，促进病毒膜与宿主膜之间的脂质混合。因此，该肽在融合过程中起关键作用，但其促进脂质混合的确切机制仍不清楚。为了阐明这一问题，我们对流感融合肽在不同环境（水、十二烷基磷酸胆碱（DPC）胶束和二肉豆蔻酰磷脂酰胆碱（DMPC）膜）中进行了分子动力学（MD）模拟。在纯水中，该肽失去了其初始二级结构，而在DPC胶束存在下进行的模拟中，它保持稳定，这与先前的实验观察结果一致。在预先组装的DMPC双层膜存在下进行的模拟中，由于所用方法的技术限制，该肽变得无结构且无法插入膜中。为了克服这个问题，我们采用了一种自组装策略，将膜与肽一起组装。这些模拟结果表明，该肽可以形成跨膜构象，这是先前MD模拟研究未预测到的。肽的插入对膜有强烈影响，降低了双层膜厚度，使附近脂质无序排列，并促进脂质尾部突出。这些结果有助于更好地理解融合肽在融合过程中的作用。
