Institute of General, Inorganic and Theoretical Chemistry, and Center for Molecular Biosciences Innsbruck (CMBI) , University of Innsbruck , Innrain 80-82 , A-6020 Innsbruck , Austria.
Biomedical Research Foundation , Academy of Athens , 4 Soranou Ephessiou , 11527 Athens , Greece.
J Phys Chem B. 2018 Nov 21;122(46):10505-10521. doi: 10.1021/acs.jpcb.8b07200. Epub 2018 Nov 8.
Computational modeling of lipid ternary mixtures is challenging because of their complicated and segmented phase diagram, the long timescales required for mixing the system components, and the necessity to sufficiently sample the three-dimensional phase space. Here, we investigate a ternary system, which mimics the lipid matrix of the stratum corneum, the outermost layer of the epidermis and the primary barrier for transdermal drug absorption. Our system consists of ceramide, cholesterol, and lignoceric acid at 23 different composition ratios, which we study at two different temperatures using coarse-grained molecular dynamics (CG MD) simulations. As CG MD simulations heavily depend on the choice of parameters, first an improved set of ceramide CG parameters was developed that reproduces experimental and all-atom simulation data. Second, the performance of the recently updated MARTINI 2015 cholesterol force field was systematically evaluated and compared to the 2007 model. We provide a detailed analysis of the structural and dynamic properties of the ternary system, such as area per lipid, area compressibility modulus, lipid order parameters, bilayer thickness, lipid tail interdigitation, and lateral self-diffusion. Based on the analysis of these properties, we devise a phase diagram of the ternary system, where three different phases, namely, liquid-disordered, gel, and liquid-ordered, are observed. The individual occurrence of a certain phase not only depends on the component molar ratio and the temperature but also decisively on the employed cholesterol force field.
研究脂质三元混合物的计算模型具有挑战性，因为它们的相图复杂且呈分段状、混合系统成分所需的时间尺度长，以及需要充分采样三维相空间。在这里，我们研究了一个三元体系，该体系模拟了表皮最外层的角质层的脂质基质和经皮药物吸收的主要屏障。我们的体系由神经酰胺、胆固醇和木质酸组成，在 23 种不同的组成比例下，我们使用粗粒分子动力学（CG MD）模拟在两种不同的温度下研究了这一体系。由于 CG MD 模拟严重依赖于参数的选择，我们首先开发了一组改进的神经酰胺 CG 参数，这些参数可以重现实验和全原子模拟数据。其次，系统地评估了最近更新的 MARTINI 2015 胆固醇力场的性能，并将其与 2007 模型进行了比较。我们提供了对三元体系的结构和动态性质的详细分析，如脂质的单位面积、面积压缩模量、脂质有序参数、双层厚度、脂质尾部互穿插和侧向自扩散。基于这些性质的分析，我们设计了三元体系的相图，其中观察到三种不同的相，即无序液体相、凝胶相和有序液体相。特定相的单独出现不仅取决于组分的摩尔比和温度，而且还取决于所采用的胆固醇力场。
