離子對雙親分子 (ion pair amphiphile, IPA) 之結構與磷脂質相似，是由兩種相異電荷之界面活性劑組成的複合分子，其成本低廉可作為仿磷脂分子。由IPA自組裝而成之陰陽離子液胞 (catanionic vesicle) 可廣泛應用於不同領域，例如藥妝、基因治療和藥物輸送等，調控IPA液胞之穩定性對於其應用發展是為重要關鍵。然目前鮮有研究針對IPA液胞與磷脂液泡之特性進行比較分析，本研究利用分子動態模擬從微觀的角度，針對長烷鏈三甲基銨鹽-長烷鏈硫酸鹽 (CnTMA+-CnS-) IPA複合分子以及磷脂醯膽鹼 (DCnPC) PC，探討其組成液泡內和液泡間的穩定度。比較IPA與PC組成之雙層膜結構，由徑向分佈函數 (RDF)、分子佔據面積、序參數 (SCD) 和間扭構形的分析顯示，IPA雙層膜具有較緊密之分子排列、較高的碳鏈序度、以及較強的機械模式。在雙層膜表面上，IPA雙層膜和水分子形成較少的氫鍵，並有較低的電位能，是由於PC分子擁有較多的親水性官能基。此外，PC分子的親水性頭基的擾動與它的疏水性碳鏈的運動有密切關聯，進一步影響水分子在親水區域的滯留時間 (τ)；然而因為PC和IPA之間親水基團結構不同，此現象在IPA雙層膜上並不顯著。我們進一步利用自由能微擾 (FEP) 計算雙親分子從IPA雙層膜溶至水溶液中所需的自由能，結果顯示長烷基鏈可以提升雙層膜之熱力學穩定度；但與PC雙層膜相比，IPA仿生膜仍具有較差的穩定度。另一方面，我們計算膜融合所需要的自由能來探討液泡間的穩定度，發現相較於PC微脂粒，IPA液胞於融合過程中，形成stalk 和fusion pore所需的自由能較低，故可推測IPA仿生液胞之液胞間穩定性較微脂粒為低。本研究自分子層次上比較PC微脂粒和IPA液胞之微觀特性，並提供未來設計仿生系統的有益資訊。

Ion pair amphiphile (IPA), a molecular complex composed of two oppositely charged surfactants, is a biomimetic amphiphile that has been proposed as a low-cost substitute for phospholipid. IPA can self-assemble into catanionic vesicles that have potentials in various fields such as cosmetic, gene therapy and drug delivery, etc. Modulating the stability of IPA vesicle is critical for its application development. Yet, there have been limited studies on the comparison between the phospholipid bilayers and the corresponding IPA membranes for the biomimetic characterizations. Here, we combined the atomistic and coarse-grained molecular dynamic simulations to investigate the intra- and inter-vesicular stabilities of vesicles composed of alkyltrimethylammonium-alkylsulfate (CnTMA+-CnS-) IPA complex and phosphatidylcholine (DCnPC). Due to the difference in the hydrophilic groups between PC and IPA, IPA bilayers exhibit denser molecular packing and higher alkyl chain ordering than the corresponding PC bilayers, as revealed by the radial distribution functions (RDF), molecular area, deuterium order parameter (SCD), and gauche conformation analyses. Meanwhile, IPA bilayers possess higher mechanical moduli, including the area compressibility modulus (KA), the molecular tilt modulus (χ), and the effective bending rigidity (KCeff) than PC bilayers. At the water-bilayer interface, IPA bilayers form fewer hydrogen bonds (H-bonds) with water and possess lower electrostatic potential than the corresponding PC bilayers, owing to more hydrophilic functional groups within a PC molecule. For the PC bilayers, the motion of hydrophobic alkyl chains closely correlate with the hydrophilic head groups motion, and longer alkyl chains prolong the water residence time (τ) at the bilayer surface. Such phenomena are less pronounced for an IPA complex, due to the hydrophilic group variations. Furthermore, we calculated the desorption free energy from the bilayer to bulk solution via the free energy perturbation (FEP) for IPA systems. Our results showed that IPA with longer alkyl chain enhances the thermodynamic stability of vesicular bilayers; yet, compared with PC membranes, IPA bilayers are still less thermodynamically stable. To probe inter-vesicular stability of IPA vesicles, we measured the membrane fusion free energy using the coarse-grained SDK model and found that IPA vesicles have lower free energy barriers for the stalk formation and the fusion pore opening compared with PC liposome. Through the comparison between PC and biomimetic IPA vesicles at the molecular level, the combined results can provide insights for future designs of biomimetic membrane systems.

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