Thermodynamic Analysis of the Effect of Cholesterol on Dipalmitoylphosphatidylcholine Lipid Membranes
Thermodynamic Analysis of the Effect of Cholesterol on Dipalmitoylphosphatidylcholine Lipid Membranes
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DOI：
10.1021/ja808541r
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发表时间：
2009-02-11
影响因子：
15
通讯作者：
Tieleman, D. Peter
中科院分区：
文献类型：
--
作者：
Bennett, W. F. Drew;MacCallum, Justin L.;Tieleman, D. Peter
胆固醇是真核细胞膜的重要组成部分。尽管有大量关于胆固醇对细胞膜的生理化学作用的文献，但关于胆固醇的确切作用及其在细胞膜中的分子相互作用仍有许多未知之处。正常的膜平面的脂质的定期热波动是生物相关的许多过程，如与酶的相互作用，弹性特性，和疏水匹配，而较大的波动涉及囊泡出芽和融合，被动脂质触发器，和孔的形成。在这里，我们使用分子动力学模拟研究胆固醇浓度对二棕榈酰磷脂酰胆碱（DPPC）双层的热力学效应。我们计算了含有20和40摩尔%胆固醇的DPPC双层中DPPC分配的平均力的潜力。增加胆固醇含量增加了DPPC的头基转移到双层中心的自由能垒，并使DPPC的翻转速率减慢了几个数量级。胆固醇增加了双层的有序性、厚度和刚性，这限制了双层的变形并防止了孔的形成。虽然DPPC触发器在纯双层中是孔介导的，但我们在20和40摩尔%双层中没有观察到孔。胆固醇浓度的增加会导致DPPC从其平衡位置转移到本体水的自由能降低，这表明DPPC更喜欢在无胆固醇的双层中。我们还观察到随着胆固醇浓度的增加，DPPC正常双层的小波动减少。
Cholesterol is an important component of eukaryotic cellular membranes. Despite extensive literature on the physiochemical effects of cholesterol on membranes, much remains unknown about the precise role of cholesterol and its molecular interactions in membranes. Regular thermal fluctuations of lipids normal to the plane of the membrane are biologically relevant for many processes, such as interactions with enzymes, elastic properties, and hydrophobic matching, while larger fluctuations are involved in vesicle budding and fusion, passive lipid flip-flop, and pore formation. Here we used molecular dynamics simulations to investigate the thermodynamic effect of the cholesterol concentration on dipalmitoylphosphatidylcholine (DPPC) bilayers. We calculated the potentials of mean force for DPPC partitioning in DPPC bilayers containing 20 and 40 mol % cholesterol. Increasing the cholesterol content increases the free energy barrier for transferring the headgroup of DPPC to the center of the bilayer and slows the rate of DPPC flip-flop by orders of magnitude. Cholesterol increases the order, thickness, and rigidity of the bilayers, which restricts bilayer deformations and prevents pore formation. While DPPC flip-flop is pore-mediated in a pure bilayer, we do not observe pores in the 20 and 40 mol % bilayers. Increasing the cholesterol concentration causes a decrease in the free energy to transfer DPPC from its equilibrium position into bulk water-indicating that DPPC prefers to be in cholesterol-free bilayers. We also observe a reduction in small fluctuations of DPPC normal to the bilayer as the cholesterol concentration is increased.