Molecular dynamics simulations of the adenosine A2a receptor: structural stability, sampling, and convergence.
Molecular dynamics simulations of the adenosine A2a receptor: structural stability, sampling, and convergence.
复制标题
腺苷 A2a 受体的分子动力学模拟：结构稳定性、采样和收敛。
DOI：
10.1021/ci300610w
复制
发表时间：
2013
影响因子：
5.6
通讯作者：
Ng HW
中科院分区：
文献类型：
--
作者：
Ng HW
近年来，膜包埋G蛋白偶联受体(GPCRs)的分子动力学(MD)模拟在分子模拟界迅速流行起来，这一趋势与这类受体的巨大药用价值和晶体结构的日益可获得性有明显的联系。鉴于这项技术的广泛使用，确保方法的可靠性和稳健性至关重要，这样才能产生有效的结果，并能够作出足够准确的预测。在这项工作中，根据这些要求，对A2a腺苷受体(A2a AR)进行了200 ns的模拟并进行了评估。在存在和不存在反向激动剂配体(ZM241385)的情况下，通过重复模拟获得了目标蛋白的构象动力学，并用主成分分析(PCA)进行了比较。结果表明，在这个时间尺度上，复制的收敛不是很明显的，并且取决于所考虑的蛋白质运动的类型。因此，与螺旋内松弛和取样相反的是，螺旋间的速率可以是不同的。当单独研究时，我们发现螺旋III和IV比载脂蛋白形式的螺旋I、II、V、VI和VII具有更大的稳定性。反向激动剂配体的加入大大提高了所有螺旋的稳定性。
Molecular dynamics (MD) simulations of membrane-embedded G-protein coupled receptors (GPCRs) have rapidly gained popularity among the molecular simulation community in recent years, a trend which has an obvious link to the tremendous pharmaceutical importance of this group of receptors and the increasing availability of crystal structures. In view of the widespread use of this technique, it is of fundamental importance to ensure the reliability and robustness of the methodologies so they yield valid results and enable sufficiently accurate predictions to be made. In this work, 200 ns simulations of the A2a adenosine receptor (A2a AR) have been produced and evaluated in the light of these requirements. The conformational dynamics of the target protein, as obtained from replicate simulations in both the presence and absence of an inverse agonist ligand (ZM241385), have been investigated and compared using principal component analysis (PCA). Results show that, on this time scale, convergence of the replicates is not readily evident and dependent on the types of the protein motions considered. Thus rates of inter- as opposed to intrahelical relaxation and sampling can be different. When studied individually, we find that helices III and IV have noticeably greater stability than helices I, II, V, VI, and VII in the apo form. The addition of the inverse agonist ligand greatly improves the stability of all helices.