How dopamine transporter interacts with dopamine: Insights from molecular modeling and simulation
How dopamine transporter interacts with dopamine: Insights from molecular modeling and simulation
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DOI：
10.1529/biophysj.107.110924
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发表时间：
2007-11-01
影响因子：
3.4
通讯作者：
Zhan, Chang-Guo
中科院分区：
文献类型：
--
作者：
Huang, Xiaoqin;Zhan, Chang-Guo
通过同源模建、分子对接和分子动力学模拟，我们建立了多巴胺转运蛋白和多巴胺转运蛋白-多巴胺复合物在脂双层和溶剂水环境中的三维结构模型。根据多巴胺转运蛋白-多巴胺复合物的模拟结构，多巴胺被定位在膜中点的疏水口袋中。模型化的3D结构提供了关于多巴胺转运蛋白（DAT）如何在原子水平上与多巴胺相互作用的一些详细的结构和机制见解，扩展了我们对Na+离子帮助下多巴胺再摄取的机制理解。模型化的三维结构的一般特征与现有的实验数据是一致的。基于模型化的结构，我们计算的多巴胺与DAT结合的结合自由能（Δ G（结合）=-6.4 kcal/mol）也合理地接近于实验导出的Δ G（结合）值-7.4 kcal/mol。最后，基于模型和分子动力学模拟结果，提出了一种可能的多巴胺进入途径，该途径涉及Arg（85）和Asp（476）侧链之间盐桥的形成和断裂.从这项计算研究中获得的新的结构和机制的见解，预计将刺激未来，进一步的生物化学和药理学研究的详细结构和机制的DAT和其他同源转运蛋白。
By performing homology modeling, molecular docking, and molecular dynamics simulations, we have developed three-dimensional (3D) structural models of both dopamine transporter and dopamine transporter-dopamine complex in the environment of lipid bilayer and solvent water. According to the simulated structure of dopamine transporter-dopamine complex, dopamine was orientated in a hydrophobic pocket at the midpoint of the membrane. The modeled 3D structures provide some detailed structural and mechanistic insights concerning how dopamine transporter (DAT) interacts with dopamine at atomic level, extending our mechanistic understanding of the dopamine reuptake with the help of Na+ ions. The general features of the modeled 3D structures are consistent with available experimental data. Based on the modeled structures, our calculated binding free energy (Delta G(bind) =-6.4 kcal/mol) for dopamine binding with DAT is also reasonably close to the experimentally derived Delta G(bind) value of -7.4 kcal/mol. Finally, a possible dopamine-entry pathway, which involves formation and breaking of the salt bridge between side chains of Arg(85) and Asp(476), is proposed based on the results obtained from the modeling and molecular dynamics simulation. The new structural and mechanistic insights obtained from this computational study are expected to stimulate future, further biochemical and pharmacological studies on the detailed structures and mechanisms of DAT and other homologous transporters.