Department of Chemistry, Faculty of Engineering and Technology, SRM Institute of Science and Technology, Kattankulathur 603203, Tamil Nadu, India.
Molecules. 2022 Aug 8;27(15):5031. doi: 10.3390/molecules27155031.
Choline geranate (CAGE) ionic liquids (ILs) stabilize insulin, thereby aiding its oral delivery, whereas ethanol (EtOH) affects its stability by disrupting the hydrophobic interactions. In this study, cognizance of the stabilization mechanism of insulin dimer in the presence of both CAGE ILs and EtOH mixtures is achieved through biased and unbiased molecular dynamics (MD) simulations. Here, two order parameters are employed to study the insulin dimer dissociation using well-tempered metadynamics (WT-MetaD). The stability of insulin is found to be strongly maintained until a 0.20 mole fraction of EtOH. Besides, higher concentrations of EtOH marginally affect the insulin stability. Moreover, geranate anions form a higher number of H-bonding interactions with water molecules, which aids insulin stabilization. Conversely, the addition of EtOH minimizes the water-mediated H-bonding interactions of geranate. Additionally, geranate traps the EtOH molecules, thereby preventing the interactions between insulin and EtOH. Furthermore, the free energy landscape (FEL) reveals the absence of dimer dissociation along with noticeable deviations in the distances R and the number of contacts Q. The dimerization free energy of insulin was calculated to be -16.1 kcal/mol at a 0.20 mole fraction of EtOH. Moreover, increments in mole fractions of EtOH effectuate a decrease in the insulin stability. Thus, the present study represents CAGE ILs as efficient insulin dimer stabilizes at low concentrations of EtOH.
胆碱生育酚（CAGE）离子液体（ILs）稳定胰岛素，从而有助于其口服递送，而乙醇（EtOH）通过破坏疏水性相互作用来影响其稳定性。在这项研究中，通过有偏见和无偏见的分子动力学（MD）模拟，认识到了 CAGE ILs 和 EtOH 混合物存在时胰岛素二聚体的稳定机制。在这里，使用了两个序参数来研究使用 well-tempered metadynamics (WT-MetaD)的胰岛素二聚体解离。发现胰岛素的稳定性直到 EtOH 的 0.20 摩尔分数都得到了很好的维持。此外，较高浓度的 EtOH 对胰岛素的稳定性只有轻微影响。此外，生育酚阴离子与水分子形成更多的氢键相互作用，从而有助于胰岛素的稳定。相反，添加 EtOH 会最小化生育酚的水介导氢键相互作用。此外，生育酚捕获 EtOH 分子，从而阻止胰岛素和 EtOH 之间的相互作用。此外，自由能景观（FEL）揭示了二聚体解离的缺失以及距离 R 和接触数量 Q 的明显偏差。在 EtOH 的 0.20 摩尔分数下，胰岛素的二聚化自由能计算为-16.1 kcal/mol。此外，EtOH 摩尔分数的增加会导致胰岛素稳定性下降。因此，本研究表明 CAGE ILs 是有效的胰岛素二聚体稳定剂，在低浓度的 EtOH 下。
