Centre for Molecular Simulation and Department of Biological Sciences, University of Calgary, Calgary, Alberta, Canada.
Centre for Molecular Simulation and Department of Biological Sciences, University of Calgary, Calgary, Alberta, Canada.
Biophys J. 2020 Apr 21;118(8):1887-1900. doi: 10.1016/j.bpj.2020.03.008. Epub 2020 Mar 20.
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.
G 蛋白偶联受体（GPCRs）是一种膜结合蛋白，其生理功能依赖于其脂质环境。许多关于几种 GPCR 脂质-蛋白相互作用模式的理论和实验研究的共同努力表明，这些受体与周围膜环境之间存在着复杂的关系，其中一些脂质尤为重要。我们使用粗粒分子动力学模拟方法，研究了 28 种不同 GPCR 的脂质-蛋白相互作用模式，涵盖了不同分类水平和构象状态，模拟总时长为 1 毫秒。我们发现，所有模拟的 GPCR 都与脂质密切相关，特别是胆固醇和磷脂酰肌醇磷酸（PIP）脂质，但这些相互作用的数量、位置和估计强度取决于特定的 GPCR 及其构象状态。虽然胆固醇和 PIP 脂质都特异性地与 GPCR 结合，但它们利用不同的机制。与 PIP 脂质的相互作用是通过与细胞内环残基的电荷-电荷相互作用介导的，并通过由环连接的两个跨膜螺旋之一或两者来稳定。另一方面，与胆固醇的相互作用是通过疏水环境介导的，通常由一个以上的螺旋中的残基组成，能够容纳其环结构，并通过与芳香族和带电/极性残基的相互作用来稳定。胆固醇与 GPCR 的结合发生在少数几个位点，其中一些（如跨膜 6/7 胞外侧的结合位点）在许多 A 类 GPCR 中共享。结合对局部膜结构的深入研究，我们的结果提供了 GPCR-脂质相互作用的详细图景。此外，我们提供了一个配套的网站，以交互方式探索所有模拟的 GPCR 的脂质-蛋白相互作用模式，以促进我们数据的分析和比较。
