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-palmitoyl,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.
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机译：众所周知，胆固醇会改变膜的物理性质和渗透性。几项先前的工作暗示细胞膜胆固醇是组织氧合的障碍，但是关于作用的机理和程度尚有很多待解释。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。我们的模拟显示出与已发布的实验数据完全一致，可以高精度再现实验血氧测定曲线的形状。我们计算的1-棕榈酰基，2-油酰基磷脂酰胆碱磷脂双层的跨膜氧渗透率上限为52±2 cm / s，接近相同厚度的水层的渗透率。随着胆固醇的添加，通透性有所降低，在62.5mol％胆固醇的近饱和水平下达到40±2 cm / s，在以实验观察到的非晶态胆固醇双层结构域的100％胆固醇模拟中达到10±2 cm / s。这些渗透率的降低仅在氧气的扩散路径不以水为主的情况下才具有生物学上的意义。在我们的模拟中，胆固醇会降低氧气在膜内的总体溶解度，但会提高膜中心附近的氧气传输参数（溶解度-扩散产物）。考虑到从膜到膜的相对较低的阻隔，我们的发现支持膜内的疏水性通道作为细胞和组织水平的氧气运输的一种方式。在这种以膜为主的扩散方案中，胆固醇对透氧性的影响足够大，值得进一步关注。
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