Notman Rebecca, Anwar Jamshed, Briels W J, Noro Massimo G, den Otter Wouter K
Molecular Biophysics, Division of Pharmaceutical Science, King's College London, London, United Kingdom.
Biophys J. 2008 Nov 15;95(10):4763-71. doi: 10.1529/biophysj.108.138545. Epub 2008 Aug 15.
Transmembrane pore formation is central to many biological processes such as ion transport, cell fusion, and viral infection. Furthermore, pore formation in the ceramide bilayers of the stratum corneum may be an important mechanism by which penetration enhancers such as dimethylsulfoxide (DMSO) weaken the barrier function of the skin. We have used the potential of mean constraint force (PMCF) method to calculate the free energy of pore formation in ceramide bilayers in both the innate gel phase and in the DMSO-induced fluidized state. Our simulations show that the fluid phase bilayers form archetypal water-filled hydrophilic pores similar to those observed in phospholipid bilayers. In contrast, the rigid gel-phase bilayers develop hydrophobic pores. At the relatively small pore diameters studied here, the hydrophobic pores are empty rather than filled with bulk water, suggesting that they do not compromise the barrier function of ceramide membranes. A phenomenological analysis suggests that these vapor pores are stable, below a critical radius, because the penalty of creating water-vapor and tail-vapor interfaces is lower than that of directly exposing the strongly hydrophobic tails to water. The PMCF free energy profile of the vapor pore supports this analysis. The simulations indicate that high DMSO concentrations drastically impair the barrier function of the skin by strongly reducing the free energy required for pore opening.
跨膜孔的形成是许多生物过程的核心，如离子运输、细胞融合和病毒感染。此外，角质层神经酰胺双层膜中孔的形成可能是一种重要机制，通过该机制，诸如二甲基亚砜（DMSO）等渗透增强剂会削弱皮肤的屏障功能。我们使用平均约束势（PMCF）方法来计算神经酰胺双层膜在天然凝胶相和DMSO诱导的流化状态下形成孔的自由能。我们的模拟表明，液相双层膜形成了典型的充满水的亲水性孔，类似于在磷脂双层膜中观察到的孔。相比之下，刚性凝胶相双层膜形成疏水性孔。在此处研究的相对较小的孔径下，疏水性孔是空的，而不是充满大量的水，这表明它们不会损害神经酰胺膜的屏障功能。现象学分析表明，这些蒸汽孔在临界半径以下是稳定的，因为形成水蒸气和尾汽界面的代价低于将强疏水尾部直接暴露于水的代价。蒸汽孔的PMCF自由能分布支持了这一分析。模拟表明，高浓度的DMSO通过大幅降低开孔所需的自由能，严重损害了皮肤的屏障功能。
