Ligand-escape pathways from the ligand-binding domain of PPARγ receptor as probed by molecular dynamics simulations
Ligand-escape pathways from the ligand-binding domain of PPARγ receptor as probed by molecular dynamics simulations
复制标题
DOI：
10.1007/s00249-007-0220-9
复制
发表时间：
2008-04-01
影响因子：
2
通讯作者：
Genest, M.
中科院分区：
文献类型：
--
作者：
Genest, D.;Garnier, N.;Genest, M.
过氧化物酶体增殖物激活受体（PPARgamma）配体结合域（LBD）的构象重排伴随着配体的释放和结合还没有得到很好的理解。为了确定与部分激动剂GW 0072逃逸相关的主要事件，使用两种不同的方法进行分子动力学（MD）模拟：反向靶向分子动力学（TMD-1）和时间依赖性距离约束（TDR），使用与参考结构（TMD-1）的均方根偏差作为约束或结合口袋和配体的几何中心之间的距离（TDR）。这两种方法都不假设任何先验的配体提取途径。为了避免伪影，使用不同的初始模拟条件，并且特别注意通过在显式水中运行10-12 ns模拟来给予蛋白质在提取过程中松弛的时间。发现了两个不同的出口门A和B，与初始条件和方法无关。在退出过程中，没有观察到GW 0072和反式激活AF-2螺旋之间的相互作用。我们的研究结果表明，配体利用蛋白质的内在灵活性在受体内移动。路径A和B与其他核受体的路径非常相似，表明这些路径是不同种类配体使用的核受体的共同特征。最后，通过将对接沿着这些途径引入到计算药物设计方案中，受体的进入/退出途径的知识在区分可能已经有利地对接在结合口袋中的不同配体方面应该是非常有用的。
Conformational rearrangements of peroxysome proliferator activated receptor (PPAR gamma) ligand-binding domain (LBD) that accompany the release and binding of ligands are not well understood. To determine the major events associated with the escape of the partial agonist GW0072, molecular dynamic (MD) simulations were performed using two different methods: reversed targeted molecular dynamics (TMD-1 ) and time-dependent distance restraints (TDR) using as restraints either the root mean square deviation from a reference structure (TMD-1 ) or the distance between the geometrical centers of the binding pocket and of the ligand (TDR). Both methods do not assume any a priori route for ligand extraction. To avoid artifacts, different initial simulation conditions were used and particular attention was paid for giving time to the protein to relax during the extraction process by running 10-12 ns simulations within explicit water. Two distinct exit gates A and B were found, independently of initial conditions and method. During the exit process no interaction between GW0072 and the transactivation AF-2 helix was observed. Our results suggest that the ligand uses the intrinsic flexibility of the protein to move within the receptor. Paths A and B are very similar to those found for other nuclear receptors, suggesting that these routes are a common characteristics of nuclear receptors that are used by different kinds of ligands. Finally, the knowledge of entry/exit pathways of a receptor should be very useful in discriminating between different ligands that could have been favorably docked in the binding pocket by introducing docking along these pathways into computational drug design protocols.