Influence of Cholesterol on the Oxygen Permeability of Membranes: Insight from Atomistic Simulations
Influence of Cholesterol on the Oxygen Permeability of Membranes: Insight from Atomistic Simulations
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DOI：
10.1016/j.bpj.2017.04.046
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发表时间：
2017-06-06
影响因子：
3.4
通讯作者：
Pias, Sally C.
中科院分区：
文献类型：
--
作者：
Dotson, Rachel J.;Smith, Casey R.;Pias, Sally C.
众所周知，胆固醇会改变膜的物理性质和通透性。先前的几项工作已经表明细胞膜胆固醇是组织氧合的屏障，但关于这种影响的机制和程度仍有很多需要解释的地方。我们使用分子动力学模拟来提供原子分辨率的洞察力，以了解胆固醇对氧在膜上和膜内扩散的影响。我们的模拟与已发表的实验数据显示出很强的整体一致性，以高精度重现了实验血氧曲线的形状。我们计算了1-棕榈酰基-1，2-油酰基磷脂酰胆碱磷脂双层膜的透氧率上限为52+/-2 cm/S，接近于相同厚度的水层的透氧率。随着胆固醇的加入，膜的通透性有所降低，在接近饱和的水平上达到40+/-2 cm/S和10+/-2 cm/S，接近饱和水平的胆固醇分别为62.5mol%和10+/-2 cm/S，与实验观察到的非晶态胆固醇双层结构域相当。这些渗透性的降低只有在氧气的扩散路径不是以水为主的情况下才会产生生物学后果。在我们的模拟中，胆固醇降低了膜内氧的总溶解度，但提高了膜中心附近的氧传输参数(溶解度-扩散积)。鉴于膜之间的传递障碍相对较低，我们的发现支持膜内疏水通道作为细胞和组织水平氧运输的一种方式。在这种膜主导的扩散方案中，胆固醇对氧气透过性的影响足够大，值得进一步关注。
Cholesterol is widely known to alter the physical properties and permeability of membranes. Several prior works have implicated cell membrane cholesterol as a barrier to tissue oxygenation, yet a good deal remains to be explained with regard to the mechanism and magnitude of the effect. We use molecular dynamics simulations to provide atomic-resolution insight into the influence of cholesterol on oxygen diffusion across and within the membrane. Our simulations show strong overall agreement with published experimental data, reproducing the shapes of experimental oximetry curves with high accuracy. We calculate the upper-limit transmembrane oxygen permeability of a 1-palmitoy1,2-oleoylphosphatidylcholine phospholipid bilayer to be 52 +/- 2 cm/s, close to the permeability of a water layer of the same thickness. With addition of cholesterol, the permeability decreases somewhat, reaching 40 +/- 2 cm/s at the near-saturating level of 62.5 mol % cholesterol and 10 +/- 2 cm/s in a 100% cholesterol mimic of the experimentally observed noncrystalline cholesterol bilayer domain. These reductions in permeability can only be biologically consequential in contexts where the diffusional path of oxygen is not water dominated. In our simulations, cholesterol reduces the overall solubility of oxygen within the membrane but enhances the oxygen transport parameter (solubility-diffusion product) near the membrane center. Given relatively low barriers to passing from membrane to membrane, our findings support hydrophobic channeling within membranes as a means of cellular and tissue-level oxygen transport. In such a membrane-dominated diffusional scheme, the influence of cholesterol on oxygen permeability is large enough to warrant further attention.