Cholesterol Flip-Flop: Insights from Free Energy Simulation Studies
Cholesterol Flip-Flop: Insights from Free Energy Simulation Studies
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DOI：
10.1021/jp108166k
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发表时间：
2010-10-28
影响因子：
3.3
通讯作者：
Im, Wonpil
中科院分区：
文献类型：
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作者：
Jo, Sunhwan;Rui, Huan;Im, Wonpil
脂质翻转运动的机制对于维持生物膜中脂质的不对称分布是重要的。为了探索被动胆固醇触发器的能量学和机制及其对链饱和度的依赖性，我们在DPPC、POPC和DAPC（二棕榈酰、棕榈酰油酰和二花生四烯酸磷脂酰胆碱）中进行了二维伞形采样模拟，并使用弦方法根据二维自由能图确定最可能的触发器路径。由此产生的路径表明，胆固醇倾向于倾斜第一，然后移动到双层中心的自由能垒存在。DAPC中的屏障比DPPC或POPC中的屏障低，并且计算出的翻转速率表明，胆固醇在多不饱和双层中的翻转比在更饱和的双层中更快。自由能垒的结果，从不利的胆固醇-水/脂质相互作用和有利的熵的贡献，由于增加脂质动力学所产生的热贡献。虽然由于所有脂质中胆固醇羟基的去溶剂化，胆固醇-水相互作用对屏障的贡献相似，但DAPC中胆固醇-脂质相互作用的屏障比DPPC或POPC低得多，导致DAPC中的自由能屏障较低。
The mechanism of lipid flip-flop motion is important for maintaining the asymmetric distribution of lipids in a biological membrane. To explore the energetics and mechanism of passive cholesterol flip-flop and its dependence on chain saturation, we performed two-dimensional umbrella sampling simulations in DPPC, POPC, and DAPC (dipalmitoyl-, palmitoyloleoyl-, and diarachidonylphosphatidylcholine) and used the string method to identify the most probable flip-flop paths based on the two-dimensional free energy maps. The resulting paths indicate that cholesterol prefers to tilt first and then move to the bilayer center where the free energy barrier exists. The barrier is lower in DAPC than in DPPC or POPC, and the calculated flip-flop rates show that cholesterol flip-flop in a poly-unsaturated bilayer is faster than in more saturated bilayers. The free energy barrier results from the unfavorable enthalpic contribution arising from cholesterol-water/lipid interactions and the favorable entropic contribution due to increased lipid dynamics. While the cholesterol-water interaction has similar contributions to the barrier due to desolvation of the cholesterol hydroxyl group in all lipids, the cholesterol-lipid interaction has a much lower barrier in DAPC than in DPPC or POPC, resulting in the lower free energy barrier in DAPC.