Comparative molecular dynamics simulations of amphotericin B-cholesterol/ergosterol membrane channels
Comparative molecular dynamics simulations of amphotericin B-cholesterol/ergosterol membrane channels
复制标题
DOI：
10.1016/s0005-2736(02)00581-3
复制
发表时间：
2002-12-23
影响因子：
3.4
通讯作者：
Borowski, E
中科院分区：
文献类型：
--
作者：
Baginski, M;Resat, H;Borowski, E
两性霉素B（AmB）是一种非常有效的抗真菌多烯大环内酯类抗生素，但其毒性限制了其使用。缺乏对AmB分子机制的完整理解阻碍了设计毒性较小的AmB衍生物的尝试。已知抗生素与存在于细胞膜中的甾醇相互作用，形成破坏膜功能的离子通道。AmB对麦角甾醇（真菌细胞中的主要甾醇）的亲和力略高于胆固醇（哺乳动物甾醇），这被认为是抗真菌化疗的最重要因素。为了在分子水平上研究这些差异，通过分子动力学（MID）模拟研究了含有AmB、固醇（胆固醇或麦角固醇）、磷脂和水分子的两个现实模型膜通道。模拟数据的比较分析表明，甾醇类型对AmB膜通道的性质有显着的影响。除了具有更大的尺寸之外，含麦角固醇的膜中的AmB通道具有更明显的分子间氢键模式。抗生素和麦角固醇之间的相互作用比抗生素和胆固醇之间的相互作用更特异。这些观察到的差异表明，含有麦角固醇的膜中的通道更稳定，并且由于其更大的尺寸，将具有更高的离子电导。这些观察结果与实验相一致。(C)2002 Elsevier Science B.V.保留所有权利。
Amphotericin B (AmB) is a very effective anti-fungal polyene macrolide antibiotic whose usage is limited by its toxicity. Lack of a complete understanding of AmB's molecular mechanism has impeded attempts to design less toxic AmB derivatives. The antibiotic is known to interact with sterols present in the cell membrane to form ion channels that disrupt membrane function. The slightly higher affinity of AmB toward ergosterol (dominant sterol in fungal cells) than cholesterol (mammalian sterol) is regarded as the most essential factor on which antifungal chemotherapy is based. To study these differences at the molecular level, two realistic model membrane channels containing molecules of AmB, sterol (cholesterol or ergosterol), phospholipid, and water were studied by molecular dynamics (MID) simulations. Comparative analysis of the simulation data revealed that the sterol type has noticeable effect on the properties of AmB membrane channels. In addition to having a larger size, the AmB channel in the ergosterol-containing membrane has a more pronounced pattern of intermolecular hydrogen bonds. The interaction between the antibiotic and ergosterol is more specific than between the antibiotic and cholesterol. These observed differences suggest that the channel in the ergosterol-containing membrane is more stable and, due to its larger size, would have a higher ion conductance. These observations are in agreement with experiments. (C) 2002 Elsevier Science B.V. All rights reserved.