LeuT conformational sampling utilizing accelerated molecular dynamics and principal component analysis.
LeuT conformational sampling utilizing accelerated molecular dynamics and principal component analysis.
复制标题
利用加速分子动力学和主成分分析进行 LeuT 构象采样。
DOI：
10.1016/j.bpj.2012.05.002
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发表时间：
2012
影响因子：
3.4
通讯作者：
Madura,JeffryD
中科院分区：
文献类型：
--
作者：
Thomas,JamesR;Gedeon,PatrickC;Grant,BarryJ;Madura,JeffryD
单胺转运体(MAT)通过将离子梯度耦合到多巴胺、去甲肾上腺素或5-羟色胺的转运体来发挥作用。尽管它们在调节神经传递方面很重要，但MATS功能的确切构象机制仍然不清楚。为此，我们对亮氨酸转运体进行了7个250 ns的加速分子动力学模拟，亮氨酸转运体是神经递质垫的模型。通过改变结合袋亮氨酸底物和钠离子的存在，我们采样了代表底物运输周期的看似合理的构象状态。使用跨膜螺旋1b和6a的主成分分析来分析得到的轨迹。这一分析揭示了七种独特的结构：其中两种构象与目前发表的晶体结构相似，一种构象类似于建议的向内开放结构，四种构象代表了对运输循环具有潜在重要性的新结构。进一步的分析表明，结合袋钠离子的存在对于稳定锁定闭塞和向内开放的构象是必要的。
Monoamine transporters (MATs) function by coupling ion gradients to the transport of dopamine, norepinephrine, or serotonin. Despite their importance in regulating neurotransmission, the exact conformational mechanism by which MATs function remains elusive. To this end, we have performed seven 250 ns accelerated molecular dynamics simulations of the leucine transporter, a model for neurotransmitter MATs. By varying the presence of binding-pocket leucine substrate and sodium ions, we have sampled plausible conformational states representative of the substrate transport cycle. The resulting trajectories were analyzed using principal component analysis of transmembrane helices 1b and 6a. This analysis revealed seven unique structures: two of the obtained conformations are similar to the currently published crystallographic structures, one conformation is similar to a proposed open inward structure, and four conformations represent novel structures of potential importance to the transport cycle. Further analysis reveals that the presence of binding-pocket sodium ions is necessary to stabilize the locked-occluded and open-inward conformations.