Metabotropic glutamate receptors (mGluRs) are class C G protein-coupled receptors that function as obligate dimers in regulating neurotransmission and synaptic plasticity in the central nervous system. The mGluR1 subtype has been shown to be modulated by the membrane lipid environment, particularly cholesterol, though the molecular mechanisms remain elusive. In this study, we employed all-atom molecular dynamics simulations to investigate the effects of cholesterol on the conformational dynamics of the mGluR1 seven transmembrane (7TM) domain in an inactive state model. Simulations were performed with three di erent cholesterol concentrations (0%, 10%, and 25%) in a palmitoyl-oleoyl phosphatidylcholine (POPC) lipid bilayer system. Our results demonstrate that cholesterol induces conformational changes in the mGluR1 dimer more significantly than in the individual protomers. Notably, cholesterol modulates the dynamics and conformations of the TM1 and TM2 helices at the dimer interface. Interestingly, an intermediate cholesterol concentration of 10% elicits more pronounced conformational changes compared to both cholesterol-depleted (0%) and cholesterol-enriched (25%) systems. Specific electrostatic interaction unique to the 10% cholesterol system further corroborate these conformational differences. Given the high sequence conservation of the 7TM domains across mGluR subtypes, the cholesterol-dependent effects observed in mGluR1 are likely applicable to other members of this receptor family. Our findings provide atomistic insights into how cholesterol modulates the conformational landscape of mGluRs, which could impact their function and signaling mechanisms.

中文翻译：

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胆固醇对代谢型谷氨酸受体 1 构象变化的依赖性

代谢型谷氨酸受体 (mGluR) 是 CG 类蛋白偶联受体，作为专性二聚体调节中枢神经系统的神经传递和突触可塑性。 mGluR1 亚型已被证明受到膜脂环境（特别是胆固醇）的调节，尽管其分子机制仍然难以捉摸。在本研究中，我们采用全原子分子动力学模拟来研究非活性状态模型中胆固醇对 mGluR1 七跨膜 (7TM) 结构域构象动力学的影响。在棕榈酰油酰磷脂酰胆碱 (POPC) 脂质双层系统中使用三种不同的胆固醇浓度（0%、10% 和 25%）进行模拟。我们的结果表明，胆固醇诱导 mGluR1 二聚体的构象变化比单个原聚体更显着。值得注意的是，胆固醇调节二聚体界面处 TM1 和 TM2 螺旋的动力学和构象。有趣的是，与不含胆固醇 (0%) 和富含胆固醇 (25%) 的系统相比，10% 的中间胆固醇浓度会引起更明显的构象变化。 10% 胆固醇系统特有的特定静电相互作用进一步证实了这些构象差异。鉴于 mGluR 亚型中 7TM 结构域的高度序列保守性，在 mGluR1 中观察到的胆固醇依赖性效应可能适用于该受体家族的其他成员。我们的研究结果为胆固醇如何调节 mGluR 的构象景观提供了原子学的见解，这可能会影响它们的功能和信号机制。