Insights into the binding of GABA to the insect RDL receptor from atomistic simulations: a comparison of models.
Insights into the binding of GABA to the insect RDL receptor from atomistic simulations: a comparison of models.
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DOI：
10.1007/s10822-013-9704-0
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发表时间：
2014-01
影响因子：
3.5
通讯作者：
Molteni, Carla
中科院分区：
文献类型：
--
作者：
Comitani, Federico;Cohen, Netta;Ashby, Jamie;Botten, Dominic;Lummis, Sarah C. R.;Molteni, Carla
关键词：
狄氏剂抗性受体（RDL）是一种昆虫五聚体配体门控离子通道（pLGIC）。它被神经递质γ-氨基丁酸（GABA）结合到其细胞外结构域激活;因此阐明这种相互作用的原子细节对于理解RDL受体如何发挥功能非常重要。由于目前没有高分辨率的结构，我们使用不同的模板，包括广泛使用的乙酰胆碱结合蛋白和两个pLGIC，欧文氏菌配体门控离子通道（ELIC）和最近解决的GluCl的RDL受体的细胞外结构域的同源模型。然后，我们将GABA对接到选定的三维结构中，我们将其用作经典分子动力学模拟的起点。这使我们能够详细分析GABA在结合位点的行为，包括它形成的氢键和阳离子-π相互作用网络，它访问的构象和水分子在介导相互作用中的可能作用;我们还估计了结合自由能。这些模型都是稳定的，并显示出共同的特征，包括与实验数据一致的相互作用和与其他pLGIC相似的相互作用;差异可归因于模型的质量，其随着序列同一性的增加而增加，以及pLGIC模板的使用。我们补充了分子动力学信息与代谢动力学，一种罕见的事件的方法，通过探索GABA结合RDL受体的自由能景观。总的来说，我们表明，GluCl模板提供了最好的模型。GABA与Arg 211和Glu 204形成直接盐桥，与包括Tyr 109、Phe 206和Tyr 254的芳香笼形成阳离子-π相互作用，代表了有利的结合排列，并且与Glu 204的相互作用也可以由水分子介导。
The resistance to dieldrin (RDL) receptor is an insect pentameric ligand-gated ion channel (pLGIC). It is activated by the neurotransmitter γ-aminobutyric acid (GABA) binding to its extracellular domain; hence elucidating the atomistic details of this interaction is important for understanding how the RDL receptor functions. As no high resolution structures are currently available, we built homology models of the extracellular domain of the RDL receptor using different templates, including the widely used acetylcholine binding protein and two pLGICs, the Erwinia Chrysanthemi ligand-gated ion channel (ELIC) and the more recently resolved GluCl. We then docked GABA into the selected three dimensional structures, which we used as starting points for classical molecular dynamics simulations. This allowed us to analyze in detail the behavior of GABA in the binding sites, including the hydrogen bond and cation-π interaction networks it formed, the conformers it visited and the possible role of water molecules in mediating the interactions; we also estimated the binding free energies. The models were all stable and showed common features, including interactions consistent with experimental data and similar to other pLGICs; differences could be attributed to the quality of the models, which increases with increasing sequence identity, and the use of a pLGIC template. We supplemented the molecular dynamics information with metadynamics, a rare event method, by exploring the free energy landscape of GABA binding to the RDL receptor. Overall, we show that the GluCl template provided the best models. GABA forming direct salt-bridges with Arg211 and Glu204, and cation-π interactions with an aromatic cage including Tyr109, Phe206 and Tyr254, represents a favorable binding arrangement, and the interaction with Glu204 can also be mediated by a water molecule.
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影响因子：
5.5
作者：
Beauchamp, Kyle A.;Lin, Yu-Shan;Das, Rhiju;Pande, Vijay S.
通讯作者：
Pande, Vijay S.
DOI：
10.1073/pnas.1007140107
发表时间：
2010-07-27
影响因子：
11.1
作者：
Blum, Angela P.;Lester, Henry A.;Dougherty, Dennis A.
通讯作者：
Dougherty, Dennis A.
影响因子：
64.8
作者：
Hilf, Ricarda J. C.;Dutzler, Raimund
通讯作者：
Dutzler, Raimund
影响因子：
3
作者：
Duan, Y;Wu, C;Kollman, P
通讯作者：
Kollman, P
DOI：
10.1107/s0907444909042073
发表时间：
2010-01
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Chen VB;Arendall WB 3rd;Headd JJ;Keedy DA;Immormino RM;Kapral GJ;Murray LW;Richardson JS;Richardson DC
通讯作者：
Richardson DC