CCR5 is a class A GPCR and serves as one of the coreceptors facilitating HIV-1 entry into host cells. This receptor has vital roles in the immune system and is involved in the pathogenesis of different diseases. Various studies were conducted to understand its activation mechanism, including structural studies in which inactive and active states of the receptor were determined in complex with various binding partners. These determined structures provided opportunities to perform molecular dynamics (MD) simulations and to analyze conformational changes observed in the protein structures. The atomic-level dynamic studies allow us to explore the effects of ionizable residues on the receptor. Here, our aim was to investigate the conformational changes in CCR5 when it forms a complex with either the inhibitor maraviroc (MRV), an approved anti-HIV drug, or HIV-1 envelope protein GP120, and compare these changes to the receptor’s apo form. In our simulations, we considered both ionized and protonated states of ionizable binding site residue GLU283^7.39 in CCR5 as the protonation state of this residue was considered ambiguously in previous studies. Our molecular simulations results suggested that in fact, the change in the protonation state of GLU283^7.39 caused interaction profiles to be different between CCR5 and its binding partners, GP120 or MRV. We observed that when the protonated state of GLU283^7.39 was considered in complex with the envelope protein GP120, there were substantial structural changes in CCR5, indicating that it adopts a more active-like conformation. On the other hand, CCR5 in complex with MRV always adopted an inactive conformation regardless of the protonation state. Hence, the CCR5 coreceptor displays conformational heterogeneity not only depending on its binding partner but also influenced by the protonation state of the binding site binding site residue GLU283^7.39. This outcome is also in accordance with some studies showing that GP120 binding could activate signaling pathways. This outcome could also have significant implications for discovering novel CCR5 inhibitors as anti-HIV drugs using in silico methods such as molecular docking, as it may be necessary to consider the protonated state of GLU283^7.39.

中文翻译：

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通过分子动力学模拟研究 GLU283 质子化态对 CCR5 构象异质性的影响


CCR5 是一种 A 类 GPCR，是促进 HIV-1 进入宿主细胞的辅助受体之一。这种受体在免疫系统中起着至关重要的作用，并参与不同疾病的发病机制。进行了各种研究以了解其激活机制，包括结构研究，其中与各种结合伴侣复合确定受体的无活性和活性状态。这些确定的结构为进行分子动力学 （MD） 模拟和分析在蛋白质结构中观察到的构象变化提供了机会。原子水平动力学研究使我们能够探索可电离残基对受体的影响。在这里，我们的目的是研究 CCR5 与抑制剂马拉韦罗 （MRV）（一种已批准的抗 HIV 药物）或 HIV-1 包膜蛋白 GP120 形成复合物时的构象变化，并将这些变化与受体的载脂蛋白形式进行比较。在我们的模拟中，我们考虑了 CCR5 中可电离结合位点残基 GLU283^7.39 的电离和质子化状态，因为在以前的研究中该残基的质子化状态被认为是模棱两可的。我们的分子模拟结果表明，事实上，GLU283^7.39 质子化状态的变化导致 CCR5 与其结合伴侣 GP120 或 MRV 之间的相互作用谱不同。我们观察到，当 GLU283^7.39 的质子化状态被认为与包膜蛋白 GP120 复合时，CCR5 的结构发生了实质性的变化，表明它采用了更活跃的构象。另一方面，与 MRV 复合的 CCR5 总是采用无活性构象，而不管质子化状态如何。 因此，CCR5 辅助受体表现出构象异质性，不仅取决于其结合伴侣，还受到结合位点结合位点残基 GLU283^7.39 的质子化状态的影响。这一结果也与一些研究表明 GP120 结合可以激活信号通路一致。这一结果也可能对使用计算机方法（如分子对接）发现新型 CCR5 抑制剂作为抗 HIV 药物具有重大意义，因为可能需要考虑 GLU283^7.39 的质子化状态。