Biomedical Engineering, University of Minnesota, Minneapolis, Minnesota 55455, USA.
J Am Chem Soc. 2011 May 4;133(17):6563-77. doi: 10.1021/ja106626r. Epub 2011 Apr 7.
In order to investigate experimentally inaccessible, molecular-level detail regarding interleaflet interaction in membranes, we have run an extensive series of coarse-grained molecular dynamics simulations of phase separated lipid bilayers. The simulations are motivated by differences in lipid and cholesterol composition in the inner and outer leaflets of biological membranes. Over the past several years, this phenomenon has inspired a series of experiments in model membrane systems which have explored the effects of lipid compositional asymmetry in the two leaflets. The simulations are directed at understanding one potential consequence of compositional asymmetry, that being regions of bilayers where liquid-ordered (L(o)) domains in one leaflet are opposite liquid-disordered (L(d)) domains in the other leaflet (phase asymmetry). The simulated bilayers are of two sorts: 1) Compositionally symmetric leaflets where each of the two leaflets contains an identical, phase separated (L(o)/L(d)) mixture of cholesterol, saturated and unsaturated phospholipid; and 2) Compositionally asymmetric leaflets, where one leaflet contains a phase separated (L(o)/L(d)) mixture while the other contains only unsaturated lipid, which on its own would be in the L(d) phase. In addition, we have run simulations where the lengths of the saturated lipid chains as well as the mole ratios of the three lipid components are varied. Collectively, we report on three types of interleaflet coupling within a bilayer. First, we show the effects of compositional asymmetry on acyl chain tilt and order, lipid rotational dynamics, and lateral diffusion in regions of leaflets that are opposite L(o) domains. Second, we show substantial effects of compositional asymmetry on local bilayer curvature, with the conclusion that phase separated leaflets resist curvature, while inducing large degrees of curvature in an opposing L(d) leaflet. Finally, in compositionally symmetric, phase separated bilayers, we find phase asymmetry (domain antiregistration) between the two leaflets occurs as a consequence of mismatched acyl chain-lengths in the saturated and unsaturated lipids.
为了研究在膜内的层间相互作用中,实验无法到达的分子水平细节,我们对相分离脂质双层进行了广泛的粗粒化分子动力学模拟。这些模拟的动机是生物膜内外叶层中脂质和胆固醇组成的差异。在过去的几年中,这种现象激发了一系列在模型膜系统中的实验,这些实验探索了双层中两个叶层中脂质组成不对称的影响。这些模拟旨在理解组成不对称的一个潜在后果,即一个叶层中的有序(L(o))域与另一个叶层中的无序(L(d))域相对(相不对称)。模拟的双层有两种类型:1)组成对称的叶层,其中两个叶层都包含相同的、相分离的(L(o)/L(d))胆固醇、饱和和不饱和磷脂混合物;2)组成不对称的叶层,其中一个叶层包含相分离的(L(o)/L(d))混合物,而另一个叶层只包含不饱和脂质,单独存在时处于 L(d)相。此外,我们还运行了模拟,其中改变了饱和脂质链的长度以及三种脂质成分的摩尔比。总的来说,我们报告了双层内三种类型的叶间耦合。首先,我们展示了组成不对称对酰基链倾斜和有序、脂质旋转动力学以及相反 L(o)域的叶层区域中脂质的横向扩散的影响。其次,我们展示了组成不对称对局部双层曲率的显著影响,得出的结论是相分离的叶层抵抗曲率,同时在相反的 L(d)叶层中诱导大的曲率。最后,在组成对称的、相分离的双层中,我们发现由于饱和和不饱和脂质的酰基链长度不匹配,两个叶层之间会发生相不对称(域反注册)。