Abstract：
Sphingosine, an amphiphilic molecule, plays a pivotal role as the core structure of sphingolipids, essential constituents of cell membranes. Its unique capability to enhance the permeability of lipid membranes profoundly influences crucial life processes. The molecular structure of sphingosine dictates its mode of entry into lipid bilayers and governs its interactions with lipids, thereby determining membrane permeability. However, the incomplete elucidation of the relationship between the molecular structure of sphingosine and the permeability of lipid membranes persists due to challenges associated with synthesizing sphingosine molecules. A series of sphingosine-derived molecules, featuring diverse hydrophobic chain lengths and distinct headgroup structure, were meticulously designed and successfully synthesized. These molecules were employed to investigate the permeability of large unilamellar vesicles, functioning as model lipid bilayers. With a decrease in the hydrophobic chain length of sphingosine from C15 to C11, the transient leakage ratio of vesicle contents escalated from ∼ 13 % to ∼ 28 %. Although the presence of double bond did not exert a pronounced influence on transient leakage, it significantly affected the continuous leakage ratio. Conversely, modifying the chirality of the C-3 hydroxyl group gives the opposite result. Notably, methylation at the C-3 hydroxyl significantly elevates transient leakage while suppressing the continuous leakage ratio. Additionally, sphingosines that significantly affect vesicle permeability tend to have a more pronounced impact on cell viability. Throughout this leakage process, the charge state of sphingosine-derived molecule aggregates in the solution emerged as a pivotal factor influencing vesicle permeability. Fluorescence lifetime experiments further revealed discernible variations in the effect of sphingosine molecular structure on the mobility of hydrophobic regions within lipid bilayers. These observed distinctions emphasize the impact of molecular structure on intermolecular interactions, extending to the microscopic architecture of membranes, and underscore the significance of subtle alterations in molecular structure and their associated aggregation behaviors in governing membrane permeability.
摘要：
鞘氨醇,两亲性分子,作为鞘脂的核心结构起着举足轻重的作用，细胞膜的主要成分。其增强脂质膜通透性的独特能力深刻地影响着至关重要的生命过程。鞘氨醇的分子结构决定了其进入脂质双层的方式，并控制了其与脂质的相互作用，从而确定膜的渗透性。然而,由于与合成鞘氨醇分子相关的挑战，鞘氨醇分子结构与脂质膜通透性之间关系的不完全阐明仍然存在。一系列鞘氨醇衍生的分子,具有不同的疏水链长度和独特的头基结构，经过精心设计和成功合成。这些分子被用来研究大单层囊泡的渗透性，充当模型脂质双层。随着鞘氨醇的疏水链长度从C15减少到C11，囊泡内容物的瞬时泄漏率从〜13％上升到〜28％。尽管双键的存在对瞬时泄漏没有明显影响，它显著影响了连续泄漏率。相反，修饰C-3羟基的手性得到相反的结果。值得注意的是,C-3羟基处的甲基化显着提高了瞬时泄漏，同时抑制了连续泄漏率。此外,显著影响囊泡通透性的鞘氨蛋白倾向于对细胞活力具有更显著的影响。在整个泄漏过程中，溶液中鞘氨醇衍生分子聚集体的电荷状态成为影响囊泡通透性的关键因素。荧光寿命实验进一步揭示了鞘氨醇分子结构对脂质双层内疏水区迁移率的影响的可辨别的变化。这些观察到的区别强调了分子结构对分子间相互作用的影响，延伸到膜的微观结构，并强调了分子结构的细微变化及其相关的聚集行为在控制膜通透性中的重要性。
