Filipe Hugo A L, Loura Luís M S, Moreno Maria João
Coimbra Chemistry Center, Institute of Molecular Sciences (CQC-IMS), University of Coimbra, 3004-535 Coimbra, Portugal.
CPIRN-IPG-Center of Potential and Innovation of Natural Resources, Polytechnic Institute of Guarda, 6300-559 Guarda, Portugal.
Membranes (Basel). 2023 May 25;13(6):551. doi: 10.3390/membranes13060551.
Permeation through biomembranes is ubiquitous for drugs to reach their active sites. Asymmetry of the cell plasma membrane (PM) has been described as having an important role in this process. Here we describe the interaction of a homologous series of 7-nitrobenz-2-oxa-1,3-diazol-4-yl (NBD)-labeled amphiphiles (NBD-Cn, = 4 to 16) with lipid bilayers of different compositions (1-palmitoyl, 2-oleoyl--glycero-3-phosphocholine (POPC):cholesterol (1:1) and palmitoylated sphingomyelin (SpM):cholesterol (6:4)), including an asymmetric bilayer. Both unrestrained and umbrella sampling (US) simulations (at varying distances to the bilayer center) were carried out. The free energy profile of NBD-Cn at different depths in the membrane was obtained from the US simulations. The behavior of the amphiphiles during the permeation process was described regarding their orientation, chain elongation, and H-bonding to lipid and water molecules. Permeability coefficients were also calculated for the different amphiphiles of the series, using the inhomogeneous solubility-diffusion model (ISDM). Quantitative agreement with values obtained from kinetic modeling of the permeation process could not be obtained. However, for the longer, and more hydrophobic amphiphiles, the variation trend along the homologous series was qualitatively better matched by the ISDM when the equilibrium location of each amphiphile was taken as reference (Δ = 0), compared to the usual choice of bulk water.
药物通过生物膜渗透到其活性部位的现象普遍存在。细胞质膜（PM）的不对称性在这一过程中被认为起着重要作用。在此，我们描述了一系列同源的7-硝基苯并-2-恶唑-1,3-二氮杂环丁烷-4-基（NBD）标记的两亲物（NBD-Cn，n = 4至16）与不同组成的脂质双层（1-棕榈酰基，2-油酰基-sn-甘油-3-磷酸胆碱（POPC）：胆固醇（1:1）和棕榈酰化鞘磷脂（SpM）：胆固醇（6:4）），包括不对称双层的相互作用。进行了无约束和伞形采样（US）模拟（在距双层中心不同距离处）。通过US模拟获得了NBD-Cn在膜中不同深度处的自由能分布。描述了两亲物在渗透过程中的行为，包括它们的取向、链伸长以及与脂质和水分子的氢键作用。还使用非均匀溶解度-扩散模型（ISDM）计算了该系列不同两亲物的渗透系数。未能获得与渗透过程动力学模型得到的值的定量一致性。然而，对于更长且更疏水的两亲物，当以每种两亲物的平衡位置作为参考（Δ = 0）时，与通常选择的本体水相比，ISDM能更好地定性匹配沿同源系列的变化趋势。
