<br>薄荷醇与人 α4β2 烟碱乙酰胆碱受体的结合通过其在膜中的强分配而得以促进。,The Journal of Physical Chemistry B

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薄荷醇与人 α4β2 烟碱乙酰胆碱受体的结合通过其在膜中的强分配而得以促进。
The Journal of Physical Chemistry B ( IF 2.8 ) Pub Date : 2020-02-12 , DOI: 10.1021/acs.jpcb.9b10092
Rezvan Shahoei ₁ , Emad Tajkhorshid ₂

Affiliation

我们利用各种计算方法来研究薄荷醇与多个有机相、脂质双层和人类 α4β2 烟碱乙酰胆碱受体 (nAChR)（大脑中最丰富的 nAChR）的相互作用。首先，在炼金自由能微扰模拟中验证为薄荷醇开发的力场参数，以计算薄荷醇在水、十二烷和辛醇中的溶剂化自由能，并将结果与实验数据进行比较。接下来，使用伞式采样构建薄荷醇渗透穿过 1-棕榈酰-2-油酰-sn-甘油-3-磷酸胆碱 (POPC) 双层的自由能曲线。旨在研究 POPC 脂质双层中薄荷醇的水膜分配的浸没模拟的结果用于确定双层中薄荷醇的渗透深度和优选方向。最后，通过对接和淹没模拟，薄荷醇被证明可以结合到人类 α4β2 nAChR 上的不同位点。薄荷醇与脱敏膜嵌入的 α4β2 nAChR 最可能的结合模式被确定为通过膜介导的途径，其中薄荷醇在膜中分配后与脂质-蛋白质界面的位点结合。还报道了一种罕见但独特的结合模式，其中薄荷醇与受体离子渗透孔的细胞外开口结合。

"点击查看英文标题和摘要"

Menthol Binding to the Human α4β2 Nicotinic Acetylcholine Receptor Facilitated by Its Strong Partitioning in the Membrane.

We utilize various computational methodologies to study menthol's interaction with multiple organic phases, a lipid bilayer, and the human α4β2 nicotinic acetylcholine receptor (nAChR), the most abundant nAChR in the brain. First, force field parameters developed for menthol are validated in alchemical free energy perturbation simulations to calculate solvation free energies of menthol in water, dodecane, and octanol and compare the results against experimental data. Next, umbrella sampling is used to construct the free energy profile of menthol permeation across a 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) bilayer. The results from a flooding simulation designed to study the water-membrane partitioning of menthol in a POPC lipid bilayer are used to determine the penetration depth and the preferred orientation of menthol in the bilayer. Finally, employing both docking and flooding simulations, menthol is shown to bind to different sites on the human α4β2 nAChR. The most likely binding mode of menthol to a desensitized membrane-embedded α4β2 nAChR is identified to be via a membrane-mediated pathway in which menthol binds to the sites at the lipid-protein interface after partitioning in the membrane. A rare but distinct binding mode in which menthol binds to the extracellular opening of receptor's ion permeation pore is also reported.

更新日期：2020-03-02

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