Characterization of the water defect at the HIV-1 gp41 membrane spanning domain in bilayers with and without cholesterol using molecular simulations.
Characterization of the water defect at the HIV-1 gp41 membrane spanning domain in bilayers with and without cholesterol using molecular simulations.
复制标题
使用分子模拟的胆固醇和不含胆固醇的双层中的HIV-1 GP41膜膜膜膜膜的表征。
DOI：
10.1016/j.bbamem.2014.01.009
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发表时间：
2014-05
期刊：
影响因子：
--
通讯作者：
Abrams CF
中科院分区：
文献类型：
--
作者：
Baker MK;Gangupomu VK;Abrams CF
人类免疫缺陷病毒1 （HIV-1）包膜糖蛋白gp41的跨膜结构域（MSD）在融合和感染中起重要作用。采用分子动力学（MD）模拟（3.4 μs）分析了α-螺旋gp41 MSD的跨中精氨酸在纯双棕榈酰磷脂酰胆碱（DPPC）和DPPC/胆固醇/ 50/50膜中被水溶剂化的膜和肽性质。我们发现中间的精氨酸被渗透到内部小叶的水溶解，导致所谓的水缺陷。水缺陷在初始条件和膜成分中表现出惊人的强健性，但胆固醇的存在在几个关键方面调节了它的行为。在含胆固醇膜中，膜厚度和水渗透深度的波动集中在跨中精氨酸附近，MSD螺旋呈现严格调节的倾斜角度。在无胆固醇膜中，厚度波动与肽位置的相关性不强，倾斜角度的变化显著取决于相对于不同厚度结构域之间边界的蛋白质位置。HIV-1病毒膜中的胆固醇是感染所必需的。因此，这项工作表明，在含胆固醇的病毒膜中，共定位的水缺陷和膜厚度波动在融合中发挥了重要作用，使膜更接近融合发生所必须跨越的稳定极限。
The membrane spanning domain (MSD) of human immunodeficiency virus 1 (HIV-1) envelope glycoprotein gp41 is important for fusion and infection. We used molecular dynamics (MD) simulations (3.4 μs total) to relate membrane and peptide properties that lead to water solvation of the α-helical gp41 MSD’s midspan arginine in pure dipalmitoylphosphatidylcholine (DPPC) and in 50/50 DPPC/cholesterol membranes. We find that the midspan arginine is solvated by water that penetrates the inner leaflet, leading to a so-called water defect. The water defect is surprisingly robust across initial conditions and membrane compositions, but the presence of cholesterol modulates its behavior in several key ways. In the cholesterol-containing membranes, fluctuations in membrane thickness and water penetration depth are localized near the midspan arginine, and the MSD helices display a tightly regulated tilt angle. In the cholesterol-free membranes, thickness fluctuations are not as strongly correlated to the peptide position and tilt angles vary significantly depending on protein position relative to boundaries between domains of differing thickness. Cholesterol in an HIV-1 viral membrane is required for infection. Therefore, this work suggests that the colocalized water defect and membrane thickness fluctuations in cholesterol-containing viral membranes play an important role in fusion by bringing the membrane closer to a stability limit that must be crossed for fusion to occur.