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首页> 外文期刊>Journal of Computer-Aided Molecular Design >Computational investigation of functional water molecules in GPCRs bound to G protein or arrestin
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Computational investigation of functional water molecules in GPCRs bound to G protein or arrestin

机译：GPCR中与G蛋白或抑制蛋白结合的功能水分子的计算研究

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G protein-coupled receptors (GPCRs) are membrane proteins constituting the largest family of drug targets. The activated GPCR binds either the heterotrimeric G proteins or arrestin through its activation cycle. Water molecules have been reported to play a role in GPCR activation. Nevertheless, reported studies are focused on the hydrophobic helical bundle region. How water molecules function in GPCR bound either G protein or arrestin is rarely studied. To address this issue, we carried out computational studies on water molecules in both GPCR/G protein complexes and GPCR/arrestin complexes. Using inhomogeneous fluid theory (IFT), we locate all possible hydration sites in GPCRs binding either to G protein or arrestin. We observe that the number of water molecules on the interaction surface between GPCRs and signal proteins are correlated with the insertion depths of the alpha 5-helix from G-protein or "finger loop " from arrestin in GPCRs. In three out of the four simulation pairs, the interfaces of Rhodopsin, M2R and NTSR1 in the G protein-associated systems show more water-mediated hydrogen-bond networks when compared to these in arrestin-associated systems. This reflects that more functionally relevant water molecules may probably be attracted in G protein-associated structures than that in arrestin-associated structures. Moreover, we find the water-mediated interaction networks throughout the NPxxY region and the orthosteric pocket, which may be a key for GPCR activation. Reported studies show that non-biased agonist, which can trigger both GPCR-G protein and GPCR-arrestin activation signal, can result in pharmacologically toxicities. Our comprehensive studies of the hydration sites in GPCR/G protein complexes and GPCR/arrestin complexes may provide important insights in the design of G-protein biased agonists.
机译：G 蛋白偶联受体 （GPCR） 是构成最大药物靶标家族的膜蛋白。激活的 GPCR 通过其激活周期结合异源三聚体 G 蛋白或抑制蛋白。据报道，水分子在GPCR活化中起作用。然而，报告的研究集中在疏水螺旋束区域。水分子如何在GPCR结合的G蛋白或抑制蛋白中发挥作用的研究很少被研究。为了解决这个问题，我们对GPCR/G蛋白复合物和GPCR/arrestin复合物中的水分子进行了计算研究。使用非均匀流体理论 （IFT），我们在与 G 蛋白或抑制蛋白结合的 GPCR 中定位所有可能的水合位点。我们观察到，GPCRs和信号蛋白相互作用表面上的水分子数量与GPCRs中来自G蛋白的α-5-螺旋或arrestin的“指环”的插入深度相关。在四个模拟对中的三个中，与抑制蛋白相关系统中的界面相比，G 蛋白相关系统中的视紫红质、M2R 和 NTSR1 界面显示出更多的水介导的氢键网络。这反映出，与抑制素相关结构相比，在G蛋白相关结构中可能被吸引的功能更相关的水分子。此外，我们还发现了整个NPxxY区域和正位袋的水介导的相互作用网络，这可能是GPCR激活的关键。据报道的研究表明，可触发 GPCR-G 蛋白和 GPCR-arrestin 激活信号的非偏倚激动剂可导致药理学毒性。我们对GPCR/G蛋白复合物和GPCR/arrestin复合物中的水合位点的综合研究可能为G蛋白偏向激动剂的设计提供重要的见解。

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