Instituto de Ciencia Molecular, Universitat de València, Spain.
J Am Chem Soc. 2009 Oct 28;131(42):15194-202. doi: 10.1021/ja904450t.
The asymmetric insertion of amphiphiles into biological membranes compromises the balance between the inner and outer monolayers. As a result, area expansion of the receiving leaflet and curvature strain may lead to membrane permeation, shape changes, or membrane fusion events. We have conducted both atomistic and coarse-grained molecular dynamics simulations of dipalmitoyl-phosphatidylcholine (DPPC) bilayers to study the effect of an asymmetric distribution of lipids between the two monolayers on membrane stability. Highly asymmetric lipid bilayers were found to be surprisingly stable within the submicrosecond time span of the simulations. Even the limiting case of a monolayer immersed in water ruptured spontaneously only after at least 20 ns simulation. A thermal shock could destabilize these kinetically trapped states. We also studied mixed systems composed of DPPC and short tail diC(8)PC lipids, showing that the presence of the cone-shaped short tail lipid facilitates the release of tension in the asymmetric systems via formation of a transmembrane pore. Thus, asymmetric area expansion and curvature stress cooperate to yield bilayer disruption. It appears that, although asymmetric area expansion destabilizes the bilayer structure, the activation energy for transmonolayer lipid re-equilibration is increased. Such a large kinetic barrier can be reduced by lipids with positive spontaneous curvature. These effects are important at the onset of bilayer destabilization phenomena, such as lipid pore formation and membrane fusion, and should be considered for the mechanism of induction of such processes by peptides and proteins.
两亲性分子在生物膜中的不对称插入破坏了内外单层之间的平衡。结果，接受小叶的面积膨胀和曲率应变可能导致膜渗透、形状变化或膜融合事件。我们对二棕榈酰磷脂酰胆碱 (DPPC) 双层进行了原子和粗粒分子动力学模拟，以研究双层中脂质不对称分布对膜稳定性的影响。高度不对称的脂质双层在模拟的亚微秒时间范围内出人意料地稳定。即使是单层浸入水中的极限情况，也至少在 20 ns 模拟后才会自发破裂。热冲击可以使这些动力学捕获态失稳。我们还研究了由 DPPC 和短尾二 C(8)PC 脂质组成的混合系统，表明锥形短尾脂质的存在通过形成跨膜孔促进了不对称系统中张力的释放。因此，不对称的面积膨胀和曲率应力共同导致双层破坏。尽管不对称的面积膨胀会破坏双层结构，但跨单层脂质再平衡的活化能增加。这种大的动力学障碍可以通过具有正自发曲率的脂质来降低。这些效应在双层失稳现象（如脂质孔形成和膜融合）的开始时很重要，并且应该考虑肽和蛋白质诱导这些过程的机制。
