Department of Chemistry, Indian Institute of Technology Delhi, Hauz Khas, New Delhi 110016, India.
Langmuir. 2022 Mar 1;38(8):2445-2459. doi: 10.1021/acs.langmuir.1c02763. Epub 2022 Feb 15.
Traditionally, liquid ethanol is known to enhance the permeability of lipid membranes and causes vesicle aggregation and fusion. However, how the amphiphilic ethanol molecules perturb the lipid vesicles to facilitate their aggregation or fusion has not been addressed at any level of molecular simulations. Herein, not only have we developed a coarse-grained (CG) model for liquid ethanol, its aqueous mixture, and hydrated lipid membranes for molecular dynamics (MD) simulations, but also utilized it to delineate the aggregation and fusion of lipid vesicles using CG-MD simulations with multimillion particles. We have systematically parametrized the force-field for pure ethanol and its interactions with hydrated POPC and POPE model lipid membranes. In this process, we have successfully reproduced the bulk ethanol structure and concentration-dependent density of aqueous ethanol. To quantify the interaction of ethanol with lipid membranes, we have reproduced the transfer free energy of the ethanol molecule across the hydrated bilayers, and the concentration-dependent distribution of ethanol molecules across the lipid bilayers. After having acceptable force-field parameters for ethanol-membrane interactions, we have checked the effect of ethanol toward the vesicles comprising POPC lipids. We observe a rapid increase in the size of the POPC lipid vesicles with increasing amounts of ethanol up to 30 mol %. We unambiguously observe swelling and decrease in the thickness of the POPC vesicles with increasing amounts of ethanol up to 30 mol %, beyond which the vesicles begin to lose their integrity and rupture at higher mol % of ethanol. The fusion study of two vesicles demonstrates that fused vesicles can be obtained from 20 to 30 mol % of ethanol provided that they are brought closer than a critical distance at a particular mol %. The multivesicle simulations show that along with the increase in the sizes of vesicles the propensity of vesicle aggregation increases as the mol % of ethanol increases.
传统上，液态乙醇被认为可以增强脂质膜的通透性，导致囊泡聚集和融合。然而，在任何分子模拟水平上，都没有解决两亲性乙醇分子如何干扰脂质囊泡以促进其聚集或融合的问题。在此，我们不仅开发了用于分子动力学 (MD) 模拟的液态乙醇、其水混合物和水合脂质膜的粗粒 (CG) 模型，还利用它通过具有数百万粒子的 CG-MD 模拟来描绘脂质囊泡的聚集和融合。我们已经系统地参数化了纯乙醇的力场及其与水合 POPC 和 POPE 模型脂质膜的相互作用。在此过程中，我们成功地再现了液体乙醇的结构和浓度依赖性的水合乙醇的密度。为了量化乙醇与脂质膜的相互作用，我们再现了乙醇分子穿过水合双层的迁移自由能，以及乙醇分子在脂质双层中浓度依赖性的分布。在获得乙醇-膜相互作用的可接受力场参数后，我们检查了乙醇对包含 POPC 脂质的囊泡的影响。我们观察到随着乙醇量的增加，POPC 脂质囊泡的尺寸迅速增大，直到 30 mol%。我们明确观察到随着乙醇量的增加，POPC 囊泡的肿胀和厚度减小，直到 30 mol%，超过该值后，囊泡开始失去完整性并在更高的乙醇摩尔%下破裂。两个囊泡的融合研究表明，只要在特定的摩尔%下将两个囊泡拉近到特定的临界距离，就可以从 20 到 30 mol%的乙醇中获得融合的囊泡。多囊泡模拟表明，随着囊泡尺寸的增加，在乙醇摩尔%增加的情况下，囊泡聚集的倾向也增加。
