離子對雙親分子（ion pair amphiphile, IPA）的自組裝形成的陰陽離子液胞可作為廉價的脂質體替代物。通過乙醇共溶劑可以增強陰陽離子液胞的形成，從而產生具有經皮藥物載體潛力的類乙醇體液胞。我們利用分子動力學（molecular dynamics, MD）模擬來檢驗乙醇共溶劑對烷基三甲基銨 - 烷基硫酸鹽IPA雙層膜在分子上的結構和機械性質的影響。我們的模擬顯示乙醇分子可進入雙層膜並位於IPA親水基團附近，導致IPA雙層膜的分子佔據面積增加和膜厚度減少。根據|SCD|與間扭構形的相關分析，增加乙醇濃度可以進一步降低IPA雙層的疏水區域內的烷基鏈排序，從而將IPA雙層膜凝膠相誘導為液態無序相。此外，乙醇共溶劑可降低IPA雙層膜的機械強度，包括面積膨脹模量，分子傾斜模量和有效彎曲剛度。在乙醇濃度高於30％體積比時，液態無序相雙層膜結構嚴重破壞，形成動態跨膜通道；此結果不同於乙醇體系統中，高乙醇濃度引起雙層膜內反微胞形成的現象。對於凝膠相IPA雙層膜系統，增加乙醇濃度可導致相變。此外，通過自由能擾動方法來計算IPA分子從膜到溶液的溶解自由能來研究IPA雙層膜的熱力學穩定性，我們的結果表明，在乙醇濃度為20體積比下，IPA雙層膜的熱力學穩定性最佳。最後為確定較低介電常數導致的IPA頭部間較強的吸引力，進而使IPA分子排列更緊密，和乙醇插入雙層膜使IPA的烷基鏈間作用力減弱，進而使IPA分子排列更鬆散這兩者的競爭性，我們利用了修飾的SDK模型加上乙醇濃度和介電常數的變化來作探討，結果表明乙醇插入雙層膜使IPA的烷基鏈間作用力減弱的有效能力更強。這項工作提供的分子見解可以為未來的新型類乙醇體IPA液胞的設計提供更多的啟示。

Catanionic vesicles formed by the self-assembly of ion pair amphiphile (IPA) have been proposed as inexpensive liposome substitutes. Formations of catanionic vesicles can be enhanced via ethanol co-solvent, resulting in the ethosome-like catanionic vesicles with promising potentials in transdermal drug delivery and cosmetics. Here, we utilized molecular dynamics (MD) simulations to examine the effects of ethanol co-solvent on the structural and mechanical properties of alkyltrimethyl-ammonium-alkylsulfate IPA bilayers at the molecular level. Our simulations showed that ethanol molecules can insert into the bilayer and locate near the IPA hydrophilic group, leading to increased molecular area and reduced membrane thickness of IPA bilayers. From the deuterium order parameter and gauche fraction analyses, increasing ethanol concentration can further reduce the alkyl chain ordering within the hydrophobic region of IPA bilayers, inducing the gel phase to the liquid-disordered phase transition of IPA bilayers. Furthermore, the ethanol co-solvent can reduce the mechanical strength of IPA bilayers, including the area expansion modulus, the molecular tilt modulus, and the effective bending rigidity. At ethanol concentration above 30 vol%, the liquid disordered phase bilayer structure is severely disrupted with the formation of dynamic transmembrane channel. Such results are different from the ethosome where high ethanol concentration induced the formation of inverse micelle within the bilayer instead. For gel phase IPA bilayer membrane systems, increasing ethanol concentration can lead to the membrane phase transition, from gel to ripple, and then to liquid disordered phase. The thermodynamics stability is also studied by using free energy perturbation to calculate the IPA molecules solvation free energy from membrane to solution. Our results indicate that at 20 vol% ethanol the vesicular IPA bilayer has the best thermodynamic stability of vesicular bilayer most. This is due to the competition between the enhanced solvophobic characteristic of the IPA polar head groups by the lowered dielectric constant and the disordered hydrocarbon chain due to the presence of ethanol. The modified SDK model coupled with variation of ethanol concentration and dielectric constant was applied to investigate the predominating factor. The result indicate a greater effect for the ethanol disordered effect. The molecular insights provided by this work can shed more light on the future designs of novel ethosome-like IPA vesicles.

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