Searching the "Biologically Relevant" Conformation of Dopamine: A Computational Approach
Searching the "Biologically Relevant" Conformation of Dopamine: A Computational Approach
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DOI：
10.1021/ci2004225
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发表时间：
2012-01-01
影响因子：
5.6
通讯作者：
Enriz, Ricardo D.
中科院分区：
文献类型：
--
作者：
Andujar, Sebastian A.;Tosso, Rodrigo D.;Enriz, Ricardo D.
本文对多巴胺（DA）与多巴胺D2受体（D2-DR）相互作用的构象势能超曲面（PEHS）进行了详尽而完整的构象研究。根据细菌视紫红质的理论模型结构，建立了人D2-DR结合口袋的简化三维模型。在我们的简化模型系统中，仅包括13种氨基酸来执行量子力学计算。为了获得DA/D2-DR的不同复合物，我们结合了半经验（PM 6），DFT（B3 LYP/6- 31 G（d））和QTAIM计算。通过势能面和势能曲线计算了DA与D2-DR相互作用的分子柔性。DA在气相中和在D2-DR下的分子柔性之间进行了比较研究。此外，进行了几个分子动力学模拟，以评估所获得的不同复合物的分子柔性。我们的研究结果使我们能够假设A型的复合物作为DA的“生物相关构象”。此外，这里报道的理论计算表明，DA发生一个机械的逐步过程，其中质子化的氮基团（在任何构象）作为锚定部分，这个过程之后是一个快速重排的构象，允许儿茶酚OH基团的相互作用。
We report here an exhaustive and complete conformational study on the conformational potential energy hypersurface (PEHS) of dopamine (DA) interacting with the dopamine D2 receptor (D2-DR). A reduced 3D model for the binding pocket of the human D2-DR was constructed on the basis of the theoretical model structure of bacteriorhodopsin. In our reduced model system, only 13 amino acids were included to perform the quantum mechanics calculations. To obtain the different complexes of DA/D2-DR, we combined semiempirical (PM6), DFT (B3LYP/6-31G(d)), and QTAIM calculations. The molecular flexibility of DA interacting with the D2-DR was evaluated from potential energy surfaces and potential energy curves. A comparative study between the molecular flexibility of DA in the gas phase and at D2-DR was carried out. In addition, several molecular dynamics simulations were carried out to evaluate the molecular flexibility of the different complexes obtained. Our results allow us to postulate the complexes of type A as the "biologically relevant conformations" of DA. In addition, the theoretical calculations reported here suggested that a mechanistic stepwise process takes place for DA in which the protonated nitrogen group (in any conformation) acts as the anchoring portion, and this process is followed by a rapid rearrangement of the conformation allowing the interaction of the catecholic OH groups.