Institut für Biophysik, Johannes Kepler Universität, Linz, Austria.
Department of Cell and Molecular Biology, Uppsala University, Uppsala, Sweden; Science for Life Laboratory, Uppsala, Sweden.
Biophys J. 2013 Dec 17;105(12):2760-70. doi: 10.1016/j.bpj.2013.11.003.
The permeability of lipid membranes for metabolic molecules or drugs is routinely estimated from the solute's oil/water partition coefficient. However, the molecular determinants that modulate the permeability in different lipid compositions have remained unclear. Here, we combine scanning electrochemical microscopy and molecular-dynamics simulations to study the effect of cholesterol on membrane permeability, because cholesterol is abundant in all animal membranes. The permeability of membranes from natural lipid mixtures to both hydrophilic and hydrophobic solutes monotonously decreases with cholesterol concentration [Chol]. The same is true for hydrophilic solutes and planar bilayers composed of dioleoyl-phosphatidylcholine or dioleoyl-phosphatidyl-ethanolamine. However, these synthetic lipids give rise to a bell-shaped dependence of membrane permeability on [Chol] for very hydrophobic solutes. The simulations indicate that cholesterol does not affect the diffusion constant inside the membrane. Instead, local partition coefficients at the lipid headgroups and at the lipid tails are modulated oppositely by cholesterol, explaining the experimental findings. Structurally, these modulations are induced by looser packing at the lipid headgroups and tighter packing at the tails upon the addition of cholesterol.
脂质膜对代谢分子或药物的通透性通常是根据溶质的油/水分配系数来估算的。然而，调节不同脂质组成中通透性的分子决定因素仍不清楚。在这里，我们结合扫描电化学显微镜和分子动力学模拟来研究胆固醇对膜通透性的影响，因为胆固醇存在于所有动物膜中。天然脂质混合物的膜对亲水性和疏水性溶质的通透性都随胆固醇浓度[Chol]单调下降。对于亲水性溶质和由二油酰基磷脂酰胆碱或二油酰基磷脂酰乙醇胺组成的平面双层膜也是如此。然而，对于非常疏水性的溶质，这些合成脂质会导致膜通透性对[Chol]呈钟形依赖性。模拟表明，胆固醇不会影响膜内的扩散常数。相反，胆固醇对脂质头部基团和脂质尾部的局部分配系数产生相反的调节，这解释了实验结果。结构上，这些调节是由于胆固醇的加入导致脂质头部基团的堆积变得松散，而脂质尾部的堆积变得紧密。
