Evotec (UK) Ltd., Abingdon, Oxfordshire, UK.
Research Department of Structural & Molecular Biology, Division of Biosciences, University College London, London, UK.
Methods Mol Biol. 2020;2114:177-186. doi: 10.1007/978-1-0716-0282-9_12.
Arrestin binding to G protein-coupled receptors (GPCRs) plays a vital role in receptor signaling. Recently, the crystal structure of rhodopsin bound to activated visual arrestin was resolved using XFEL (X-ray free electron laser). However, even with the crystal structure in hand, our ability to understand GPCR-arrestin binding is limited by the availability of accurate tools to explore receptor-arrestin interactions. We applied fragment molecular orbital (FMO) method to explore the interactions formed between the residues of rhodopsin and arrestin. FMO enables ab initio approaches to be applied to systems that conventional quantum mechanical (QM) methods would be too compute-expensive. The FMO calculations detected 35 significant interactions involved in rhodopsin-arrestin binding formed by 25 residues of rhodopsin and 28 residues of arrestin. Two major regions of interaction were identified: at the C-terminal tail of rhodopsin (D330-S343) and where the "finger loop" (G69-T79) of arrestin directly inserts into rhodopsin active core. Out of these 35 interactions, 23 were mainly electrostatic and 12 hydrophobic in nature.
视蛋白与激活状态的视觉 arrestin 结合的晶体结构使用 XFEL（X 射线自由电子激光）得到解析。然而，即使有了晶体结构，我们理解 GPCR-arrestin 结合的能力仍然受到探索受体- arrestin 相互作用的准确工具的可用性的限制。我们应用片段分子轨道（FMO）方法来探索视蛋白和 arrestin 之间形成的相互作用。FMO 使从头计算方法能够应用于传统量子力学（QM）方法计算成本过高的系统。FMO 计算检测到 35 个对视蛋白-arrestin 结合至关重要的相互作用，这些相互作用由视蛋白的 25 个残基和 arrestin 的 28 个残基形成。鉴定出两个主要的相互作用区域：视蛋白的 C 末端尾部（D330-S343）和 arrestin 的“指环”（G69-T79）直接插入视蛋白活性核心的部位。在这 35 个相互作用中，23 个主要是静电相互作用，12 个是疏水相互作用。
