Li Zhenlong, Gorfe Alemayehu A
Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, 6431 Fannin St., Houston, Texas 77030.
Soft Matter. 2013 Dec 21;9(47). doi: 10.1039/C3SM51388B.
Ras proteins are attached to the inner leaflet of the plasma membrane via a lipid-modified anchor. Membrane-bound Ras proteins laterally segregate into nanoscale signaling platforms called nanoclusters. It has been shown that the membrane domain preference of Ras nanoclusters varies with the nature of lipidation but their effect on the membrane has not been well understood. To investigate the effect of Ras insertion on membrane structure, we carried out numerous coarse-grained molecular dynamics (CGMD) simulations on a two-domain DPPC/DLiPC/cholesterol lipid bilayer in which different number and type of H-ras peptides were attached on one side. We have shown previously that this lipid mixture forms co-existing liquid-ordered/liquid-disordered (L /L ) domains and that different H-ras peptides form clusters that variously accumulate at the L /L regions or the boundary between them. Here we show that asymmetric insertion of each of these peptides induces a vertical relative displacement of the domains and deforms the bilayer, with the domain boundary serving as the center of deformation. The extent of the deformation, however, varies with the type and number of lipid modification. This is because the number and type of the Ras lipid tails determines the degree to which the stress caused by asymmetric peptide insertion is relieved by inter-leaflet cholesterol transfer and lipid tilt. In addition, we have characterized the mechanism of bilayer deformation based on the collective effect of the Ras peptides on inter-leaflet surface area, pressure profile and line tension differences. This allowed us to elucidate how Ras lipid modification affects membrane geometry and how a two-domain bilayer adjusts its shape through boundary deformation. The result contributes to a better understanding of Ras signaling platforms and highlights some of the mechanisms by which a multi-domain membrane responds to external perturbation.
Ras蛋白通过脂质修饰的锚定基团附着于质膜的内小叶。膜结合的Ras蛋白横向分离形成称为纳米簇的纳米级信号平台。研究表明，Ras纳米簇的膜结构域偏好随脂质化性质而变化，但其对膜的影响尚未得到很好的理解。为了研究Ras插入对膜结构的影响，我们对一个双结构域的二棕榈酰磷脂酰胆碱/二月桂酰磷脂酰胆碱/胆固醇脂质双层进行了大量的粗粒度分子动力学（CGMD）模拟，其中一侧附着了不同数量和类型的H-ras肽。我们之前已经表明，这种脂质混合物形成共存的有序液相/无序液相（L /L ）结构域，并且不同的H-ras肽形成簇，这些簇在L /L 区域或它们之间的边界处不同程度地聚集。在这里，我们表明这些肽中的每一种的不对称插入都会引起结构域的垂直相对位移并使双层变形，结构域边界作为变形中心。然而，变形程度随脂质修饰的类型和数量而变化。这是因为Ras脂质尾部的数量和类型决定了由不对称肽插入引起的应力通过叶间胆固醇转移和脂质倾斜得以缓解的程度。此外，我们基于Ras肽对叶间表面积、压力分布和线张力差异的集体效应，表征了双层变形的机制。这使我们能够阐明Ras脂质修饰如何影响膜几何形状，以及双结构域双层如何通过边界变形来调整其形状。该结果有助于更好地理解Ras信号平台，并突出了多结构域膜对外界扰动作出反应的一些机制。
