Transport of nucleosides in the vcCNT facilitated by sodium gradients from molecular dynamics simulations
Transport of nucleosides in the vcCNT facilitated by sodium gradients from molecular dynamics simulations
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分子动力学模拟中钠梯度促进 vcCNT 中核苷的传输
DOI：
10.1039/c3mb70126c
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发表时间：
2013-01-01
影响因子：
--
通讯作者：
Li, Youyong
中科院分区：
文献类型：
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作者：
Feng, Zhiwei;Hou, Tingjun;Li, Youyong
核苷是DNA和RNA合成所必需的，并且核苷腺苷在各种信号传导过程中具有功能。核苷需要一类专门的整合膜蛋白，称为核苷转运蛋白（NT），用于跨细胞膜的特异性转运。NT也是核苷衍生药物跨细胞膜转运的重要决定因素。最近，报道了vcCNT（霍乱弧菌浓缩核苷转运蛋白）的晶体结构。在这里，我们进行分子动力学（MD）模拟的vcCNT结构中存在的各种钠梯度，因为碳纳米管钠耦合转运。结果突出了与vcCNT结合的钠在尿苷转运中的重要作用。我们的MD模拟表明，在没有NaCl的情况下，尿苷在vcCNT的结合口袋中保持稳定。在20 mM NaCl的存在下，尿苷从结合口袋移动并接近细胞内侧的入口。在100 mM NaCl的存在下，尿苷通过入口的大部分并接近细胞内侧。结合口袋中的极性/带电氨基酸在转运过程中很重要。它们首先“固定”核糖并允许尿苷的尿嘧啶碱基接近细胞内侧的入口，然后“释放”核糖以允许尿苷与钠离子和HP 1b的运动耦合地自由移动到细胞内侧。最后，我们提出了一个详细的机制的核苷运输从结合口袋的细胞内侧的vcCNT。
Nucleosides are required for DNA and RNA synthesis, and the nucleoside adenosine has a function in a variety of signaling processes. Nucleosides require a specialized class of integral membrane proteins, known as nucleoside transporters (NTs), for specific transport across cell membranes. NTs are also important determinants for the transport of nucleoside-derived drugs across cell membranes. Recently, the crystal structure of the vcCNT (Vibrio cholerae Concentrative Nucleoside Transporter) was reported. Here we perform molecular dynamics (MD) simulations for the vcCNT structure in the presence of various sodium gradients, since CNTs are sodium-coupled transporters. The results highlight the important role of sodium bound to the vcCNT in the transport of uridine. Our MD simulations show that, without NaCl, uridine remains stable in the binding pocket of the vcCNT. In the presence of 20 mM NaCl, uridine moves from the binding pocket and approaches the entrance of the intracellular side. In the presence of 100 mM NaCl, uridine passes through most part of the entrance and approaches the intracellular side. The polar/charged amino acids in the binding pocket are important in the transport process. They first "fix" the ribose and allow the uracil base of uridine to approach the entrance of the intracellular side, and then "release" the ribose to allow uridine to move freely into the intracellular side coupled with the movement of sodium ions and HP1b. Finally, we propose a detailed mechanism of the nucleoside transport from the binding pocket to the intracellular side of the vcCNT.