G protein-coupled receptors (GPCRs) are membrane-bound proteins that depend on their lipid environment to carry out their physiological function. Combined efforts from many theoretical and experimental studies on the lipid-protein interaction profile of several GPCRs hint at an intricate relationship of these receptors with their surrounding membrane environment, with several lipids emerging as particularly important. Using coarse-grained molecular dynamics simulations, we explore the lipid-protein interaction profiles of 28 different GPCRs, spanning different levels of classification and conformational states and totaling to 1 ms of simulation time. We find a close relationship with lipids for all GPCRs simulated, in particular, cholesterol and phosphatidylinositol phosphate (PIP) lipids, but the number, location, and estimated strength of these interactions is dependent on the specific GPCR as well as its conformational state. Although both cholesterol and PIP lipids bind specifically to GPCRs, they utilize distinct mechanisms. Interactions with PIP lipids are mediated by charge-charge interactions with intracellular loop residues and stabilized by one or both of the transmembrane helices linked by the loop. Interactions with cholesterol, on the other hand, are mediated by a hydrophobic environment, usually made up of residues from more than one helix, capable of accommodating its ring structure and stabilized by interactions with aromatic and charged/polar residues. Cholesterol binding to GPCRs occurs in a small number of sites, some of which (like the binding site on the extracellular side of transmembrane 6/7) are shared among many class A GPCRs. Combined with a thorough investigation of the local membrane structure, our results provide a detailed picture of GPCR-lipid interactions. Additionally, we provide an accompanying website to interactively explore the lipid-protein interaction profile of all GPCRs simulated to facilitate analysis and comparison of our data.

中文翻译：

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脂蛋白相互作用是 G 蛋白偶联受体的独特特性和决定性特征

G 蛋白偶联受体 (GPCR) 是膜结合蛋白，依赖于其脂质环境来执行其生理功能。对几种 GPCR 的脂质-蛋白质相互作用谱的许多理论和实验研究的综合努力暗示了这些受体与其周围膜环境的错综复杂的关系，其中几种脂质尤为重要。使用粗粒度分子动力学模拟，我们探索了 28 种不同 GPCR 的脂质-蛋白质相互作用谱，跨越不同级别的分类和构象状态，模拟时间总计 1 毫秒。我们发现所有模拟的 GPCR 与脂质密切相关，特别是胆固醇和磷酸肌醇 (PIP) 脂质，但数量、位置、这些相互作用的估计强度取决于特定的 GPCR 及其构象状态。尽管胆固醇和 PIP 脂质都与 GPCR 特异性结合，但它们利用不同的机制。与 PIP 脂质的相互作用由与细胞内环残基的电荷-电荷相互作用介导，并由环连接的一个或两个跨膜螺旋稳定。另一方面，与胆固醇的相互作用是由疏水环境介导的，疏水环境通常由来自多个螺旋的残基组成，能够适应其环结构，并通过与芳香族和带电/极性残基的相互作用而稳定。胆固醇与 GPCR 的结合发生在少数位点，其中一些位点（如跨膜 6/7 细胞外侧的结合位点）在许多 A 类 GPCR 之间共享。结合对局部膜结构的彻底调查，我们的结果提供了 GPCR-脂质相互作用的详细图片。此外，我们提供了一个随附的网站，以交互方式探索模拟的所有 GPCR 的脂质-蛋白质相互作用概况，以促进我们数据的分析和比较。