Karlsen Maria Lyngby, Bruhn Dennis S, Pezeshkian Weria, Khandelia Himanshu
PHYLIFE: Physical Life Science, Department of Physics, Chemistry and Pharmacy, University of Southern Denmark Campusvej 55 Odense 5230 M Denmark
RSC Adv. 2021 Jun 28;11(37):22677-22682. doi: 10.1039/d1ra01464a. eCollection 2021 Jun 25.
The transbilayer distribution of cholesterol (CHL) in complex asymmetric lipid membranes remains controversial, with contrasting investigations suggesting that there is more CHL either in the exoplasmic, outer leaflet (OL) or the cytoplasmic, inner leaflet (IL) depending on cell type or model, membrane composition, and method of investigation. Here, we launch systematic coarse-grained molecular dynamics simulations to investigate the impact of the sphingomyelin (SM) acyl chain length upon CHL distribution in asymmetric lipid membrane mixtures which account for the variation of the most abundant headgroups and acyl chain unsaturation in the two membrane leaflets. We find that there is always more CHL in the OL, but longer chain SM depletes more CHL from the IL than short chain SM in simple membrane mixtures containing SM and 16 : 0, 18 : 1 phospholipids. The difference between longer and shorter chain SM is neutralised in a more complex asymmetric membrane, where there are more saturated tails in the outer leaflet. We propose that interdigitation of long-chain SM into the opposing IL pushes cytoplasmic CHL towards the OL, but higher chain saturation of the outer leaflet compensates for the effect of SM chain length.
胆固醇(CHL)在复杂的不对称脂质膜中的跨膜分布仍存在争议,相互矛盾的研究表明,根据细胞类型或模型、膜组成和研究方法的不同,外质外侧小叶(OL)或细胞质内侧小叶(IL)中存在更多的CHL。在此,我们开展了系统的粗粒度分子动力学模拟,以研究鞘磷脂(SM)酰基链长度对不对称脂质膜混合物中CHL分布的影响,该混合物考虑了两个膜小叶中最丰富的头部基团和酰基链不饱和度的变化。我们发现,在含有SM和16:0、18:1磷脂的简单膜混合物中,OL中总是存在更多的CHL,但长链SM比短链SM从IL中消耗更多的CHL。在更复杂的不对称膜中,长链和短链SM之间的差异被抵消,其中外侧小叶中有更多的饱和尾部。我们提出,长链SM插入相对的IL中会将细胞质CHL推向OL,但外侧小叶中更高的链饱和度补偿了SM链长度的影响。