Free energy landscape of G-protein coupled receptors, explored by accelerated molecular dynamics.
Free energy landscape of G-protein coupled receptors, explored by accelerated molecular dynamics.
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DOI：
10.1039/c3cp53962h
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发表时间：
2014-04-14
期刊：
影响因子：
--
通讯作者：
McCammon JA
中科院分区：
文献类型：
--
作者：
Miao Y;Nichols SE;McCammon JA
G蛋白偶联受体（GPCR）介导细胞对各种激素和神经递质的反应，是治疗多种疾病的重要靶点。G蛋白偶联受体（GPCR）介导细胞对各种激素和神经递质的反应，是治疗多种疾病的重要靶点。已知它们采用多种构象状态（例如，非活性的、中间的和活性的）。在这里，使用加速分子动力学（aMD）模拟来探索GPCR的自由能景观，如M2毒蕈碱受体（一种调节人类心率和心肌细胞收缩力的关键GPCR）所示。详细分析了在GPCR激活和变构信号传导时经历构象转变的重要结构基序的自由能谱，包括Arg3.50-Glu6.30离子锁，Trp6.48拨动开关和Tyr5.58-Tyr7.53之间的氢相互作用。
G-protein coupled receptors (GPCRs) mediate cellular responses to various hormones and neurotransmitters and are important targets for treating a wide spectrum of diseases. G-protein coupled receptors (GPCRs) mediate cellular responses to various hormones and neurotransmitters and are important targets for treating a wide spectrum of diseases. They are known to adopt multiple conformational states (e.g., inactive, intermediate and active) during their modulation of various cell signaling pathways. Here, the free energy landscape of GPCRs is explored using accelerated molecular dynamics (aMD) simulations as demonstrated on the M2 muscarinic receptor, a key GPCR that regulates human heart rate and contractile forces of cardiomyocytes. Free energy profiles of important structural motifs that undergo conformational transitions upon GPCR activation and allosteric signaling are analyzed in detail, including the Arg3.50–Glu6.30 ionic lock, the Trp6.48 toggle switch and the hydrogen interactions between Tyr5.58–Tyr7.53.
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影响因子：
16.6
作者：
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通讯作者：
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影响因子：
3.3
作者：
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作者：
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通讯作者：
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DOI：
10.1073/pnas.0811065106
发表时间：
2009-03-24
影响因子：
11.1
作者：
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通讯作者：
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