Insights from molecular dynamics: the binding site of cocaine in the dopamine transporter and permeation pathways of substrates in the leucine and dopamine transporters.
Insights from molecular dynamics: the binding site of cocaine in the dopamine transporter and permeation pathways of substrates in the leucine and dopamine transporters.
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DOI：
10.1016/j.jmgm.2012.05.007
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发表时间：
2012-09
影响因子：
2.9
通讯作者：
Madura, Jeffry D.
中科院分区：
文献类型：
--
作者：
Merchant, Bonnie A.;Madura, Jeffry D.
多巴胺转运体（DAT）有助于调节突触神经递质水平。作为抗抑郁药和可卡因等治疗性及非法精神兴奋剂药物的作用靶点，DAT已被深入研究。尽管有大量关于DAT的突变和生理数据，但其结构仍未解析，转运机制、结合位点和构象变化的细节仍存在争议。DAT的一种细菌同源物，亮氨酸转运体（LeuTAa）已被用作模拟和理解DAT的模板和框架。从多构象热力学积分获得的自由能曲线使我们能够正确识别LeuTAa的主要和次要结合口袋。对DAT中多巴胺和可卡因的自由能曲线进行比较表明，可卡因的结合位点位于一个次要口袋，而非主要底物位点。使用随机加速分子动力学方法在这两种转运体中都确定了从主要口袋向细胞内释放底物的两条常见的主要途径。一条途径似乎沿着跨膜结构域（TMs）1a和6b，而另一条途径沿着TMs 6b和8。有趣的是，我们观察到在两种模拟类型中，单个钠离子都与亮氨酸共同转运。
The dopamine transporter (DAT) facilitates the regulation of synaptic neurotransmitter levels. As a target for therapeutic and illicit psycho-stimulant drugs like antidepressants and cocaine, DAT has been studied intensively. Despite a wealth of mutational and physiological data regarding DAT, the structure remains unsolved and details of the transport mechanism, binding sites and conformational changes remain debated. A bacterial homologue of DAT, the leucine transporter (LeuTAa) has been used as a template and framework for modeling and understanding DAT. Free energy profiles obtained from Multi-Configuration Thermodynamic Integration allowed us to correctly identify the primary and secondary binding pockets of LeuTAa. A comparison of free energy profiles for dopamine and cocaine in DAT suggests that the binding site of cocaine is located in a secondary pocket, not the primary substrate site. Two recurring primary pathways for intracellular substrate release from the primary pocket are identified in both transporters using the Random Acceleration Molecular Dynamics method. One pathway appears to follow transmembranes (TMs) 1a and 6b while the other pathway follows along TMs 6b and 8. Interestingly, we observe that a single sodium ion is co-transported with leucine during both simulations types.
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