基于各项异性网络模型研究μ阿片受体的动力学及关键位点

Study on the Dynamics and Key Sites of the μ-Opioid Receptor Based on the Anisotropic Network Model

摘要: 阿片类药物主要通过选择性作用于μ阿片受体(μ-opioid receptor, MOR)，激活抑制性G蛋白来实现镇痛的效果。由于其使用常伴随成瘾、呼吸抑制等严重的不良反应，针对阿片受体的药物研发成为一大挑战。为研究MOR的结构动力学和功能性关键位点，首先基于各向异性网络模型(Anisotropic network model, ANM)分析低频、高频运动模式下的残基涨落以及残基间的交叉相关涨落；然后，构造氨基酸复杂网络识别与变构信号传导相关的关键残基。结果表明，慢运动模式可有效识别结构中的功能区域，快运动模式能够识别对稳定MOR非活性结构重要的热点残基，运动相关性分析则揭示了跨膜螺旋区域变构信号的转导机制。另外，复杂网络识别出的关键残基在配体结合和信号传递中起重要作用。本工作有助于理解μ阿片受体的动力学特性和关键位点，并为药物设计提供有益的参考信息。

Abstract: Opioids mainly achieve analgesic effects by selectively acting on μ-opioid receptors (MOR) and activating inhibitory G proteins. Since its use is often accompanied by serious adverse reactions such as addiction and respiratory depression, the development of drugs targeting opioid receptors has become a major challenge. To investigate the structural dynamics and functional key sites of MOR, we first analyzed the residue fluctuations under low-frequency and high-frequency motion modes and the cross-correlation fluctuations between residues based on the Anisotropic network model (ANM). Then, a complex network of amino acids is constructed to identify key residues associated with allosteric signaling. The results showed that the lowest mode effectively identified functional regions within the structure, the fastest mode identified hotspot residues important for stabilizing the MOR inactive structure, and motion correlation analysis revealed the transduction mechanism of allosteric signals in the transmembrane helical region. Additionally, the complex network identified key residues that play important roles in ligand binding and signaling. This work helps to understand the dynamics characteristics and key sites of μ-opioid receptors, and provides useful reference information for drug design.