高压对NMDA受体的影响：分子动力学模拟。,Scientific Reports

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高压对NMDA受体的影响：分子动力学模拟。
Scientific Reports ( IF 3.8 ) Pub Date : 2019-07-25 , DOI: 10.1038/s41598-019-47102-x
Alice Bliznyuk _{1,

2} , Yoram Grossman ₂ , Yevgeny Moskovitz ₃

Affiliation

暴露在高于11 bar的环境压力下的专业潜水员会出现高压神经系统综合症（HPNS），表现为中枢神经系统（CNS）过度兴奋，运动障碍，感觉障碍和认知缺陷。谷氨酸型N-甲基-D-天冬氨酸受体（NMDAR）已被认为与HPNS的中枢神经系统过度兴奋有关。包含不同亚基的NMDAR在高压下表现出不同程度的增加/减少的电流。造成这种现象的机理尚不清楚。我们对嵌入在1 bar水压，25 bar静水压力和25 bar氦气中的油酰磷脂酰胆碱（DOPC）脂质双层中的NMDAR结构进行了100 ns的分子动力学（MD）模拟。MD仿真显示，与静水压力相比，高压氦气会由于其在两个单层之间的堆积而引起DOPC膜的严重变形：Sn-1和Sn-2 DOPC链的还原以及NMDAR孔的氦气依赖性脱水。进一步分析NMDAR蛋白的重要区域，例如孔表面（M2α-螺旋），Mg2 +结合位点和TMD-M4α-螺旋，显示出显着的氦气作用。与以前的模型相比，这些和我们先前的结果表明，高压氦本身而不是静水压力本身通过蛋白质-脂质相互作用改变了受体的三级结构。潜水员呼吸混合物中的氦气可能部分导致HPNS症状。进一步分析NMDAR蛋白的重要区域，例如孔表面（M2α-螺旋），Mg2 +结合位点和TMD-M4α-螺旋，显示出显着的氦气作用。与以前的模型相比，这些和我们先前的结果表明，高压氦本身而不是静水压力本身通过蛋白质-脂质相互作用改变了受体的三级结构。潜水员呼吸混合物中的氦气可能部分导致HPNS症状。进一步分析NMDAR蛋白的重要区域，例如孔表面（M2α-螺旋），Mg2 +结合位点和TMD-M4α-螺旋，显示出显着的氦气作用。与以前的模型相比，这些和我们先前的结果表明，高压氦本身而不是静水压力本身通过蛋白质-脂质相互作用改变了受体的三级结构。潜水员呼吸混合物中的氦气可能部分导致HPNS症状。

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The effect of high pressure on the NMDA receptor: molecular dynamics simulations.

Professional divers exposed to ambient pressures above 11 bar develop the high pressure neurological syndrome (HPNS), manifesting as central nervous system (CNS) hyperexcitability, motor disturbances, sensory impairment, and cognitive deficits. The glutamate-type N-methyl-D-aspartate receptor (NMDAR) has been implicated in the CNS hyperexcitability of HPNS. NMDARs containing different subunits exhibited varying degrees of increased/decreased current at high pressure. The mechanisms underlying this phenomenon remain unclear. We performed 100 ns molecular dynamics (MD) simulations of the NMDAR structure embedded in a dioleoylphosphatidylcholine (DOPC) lipid bilayer solvated in water at 1 bar, hydrostatic 25 bar, and in helium at 25 bar. MD simulations showed that in contrast to hydrostatic pressure, high pressure helium causes substantial distortion of the DOPC membrane due to its accumulation between the two monolayers: reduction of the Sn-1 and Sn-2 DOPC chains and helium-dependent dehydration of the NMDAR pore. Further analysis of important regions of the NMDAR protein such as pore surface (M2 α-helix), Mg2+ binding site, and TMD-M4 α-helix revealed significant effects of helium. In contrast with previous models, these and our earlier results suggest that high pressure helium, not hydrostatic pressure per se, alters the receptor tertiary structure via protein-lipid interactions. Helium in divers' breathing mixtures may partially contribute to HPNS symptoms.

更新日期：2019-07-25

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