Simulations of Diabetic and Non-Diabetic Peripheral Nerve Myelin Lipid Bilayers
Simulations of Diabetic and Non-Diabetic Peripheral Nerve Myelin Lipid Bilayers
复制标题
糖尿病和非糖尿病周围神经髓磷脂双层的模拟
DOI：
10.1021/acs.jpcb.1c01621
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Klauda, Jeffery B.
中科院分区：
文献类型：
--
作者：
Yuan, Yiding;Yu, Yalun;Klauda, Jeffery B.
多层髓鞘是中枢和外周神经系统的重要组成部分，形成保护屏障以防止轴突损伤并促进神经冲动的运动。主要由胆固醇（CHL 1）、磷脂酰胆碱（PC）、磷脂酰乙醇胺（PE）、磷脂酰丝氨酸（PS）、磷脂酰肌醇（PI）、鞘磷脂（SM）和半乳糖神经酰胺（GalCer）脂质组成。对于大鼠坐骨神经髓磷脂（周围神经系统的一部分，PNS），已经发现糖尿病患者的胆固醇和不饱和脂肪酸含量显著低于非糖尿病患者。在这项研究中，从实验数据的脂质组合物被用来创建四个模型大鼠坐骨神经髓鞘脂质双层：PI含（非糖尿病和糖尿病）和PS含（非糖尿病和糖尿病），然后使用全原子CHARMM 36力场模拟。糖尿病膜的模拟结果表明，刚性较低，更横向扩张，和更薄的双层，以及潜在的减少之间的相互作用的GalCer对相对的髓鞘小叶，支持的直接作用的胆固醇含量的降低，在煽动髓鞘恶化和糖尿病周围神经病变。与PI-脂质相比，PS-脂质被发现导致更高的脂质间间距和膜内的有序度降低，这是由于它们的较小的头基尺寸和更高的脂质间氢键结合势，这使得它们更频繁地驻留在膜平面的更深处，并对其他脂质产生推动作用。GalCer氘序参数和非糖尿病头基-头基双层厚度与实验数据进行了比较，显示出紧密的对齐，支持未来使用这些模型来研究PNS髓鞘。
The multilayered myelin sheath is a critical component of both central and peripheral nervous systems, forming a protective barrier against axonal damage and facilitating the movement of nervous impulses. It is primarily composed of cholesterol (CHL1), phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylserine (PS), phosphatidylinositol (PI), sphingomyelin (SM), and galactosylceramide (GalCer) lipids. For rat sciatic nerve myelin (part of the peripheral nervous system, PNS), it has been found that cholesterol and unsaturated fatty acid contents are significantly lower in diabetic than in non-diabetic conditions. In this study, lipid compositions from experimental data are used to create four model rat sciatic nerve myelin lipid bilayers: PI-containing (non-diabetic and diabetic) and PS-containing (non-diabetic and diabetic), which were then simulated using the all-atom CHARMM36 force field. Simulation results of diabetic membranes indicate less rigid, more laterally expansive, and thinner bilayers as well as potentially reduced interactions between GalCer on opposing myelin leaflets, supporting a direct role of the cholesterol content decrease in instigating myelin deterioration and diabetic peripheral neuropathy. Compared to PI-lipids, PS-lipids were found to cause higher inter-lipid spacing and decreased order within membranes as a result of their smaller headgroup size and higher inter-lipid hydrogen bonding potential, which allow them to more frequently reside deeper in the membrane plane and produce pushing effects on other lipids. GalCer deuterium order parameters and non-diabetic headgroup-to-headgroup bilayer thicknesses were compared to experimental data, exhibiting close alignment, supporting the future usage of these models to study the PNS myelin sheath.