Theoretical examination of two opposite mechanisms proposed for hepatitis delta virus ribozyme.
Theoretical examination of two opposite mechanisms proposed for hepatitis delta virus ribozyme.
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DOI：
10.1021/jp070120u
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发表时间：
2007-01
期刊：
影响因子：
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通讯作者：
Kai Wei;Lei Liu;Yu-Hui Cheng;Yao Fu;Q. Guo
中科院分区：
文献类型：
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作者：
Kai Wei;Lei Liu;Yu-Hui Cheng;Yao Fu;Q. Guo
对于丁型肝炎病毒（HDV）核酶，先前提出了两种机制，其中活性位点胞嘧啶残基（C75）作为通用碱基以使断裂位点处的2 '-OH去质子化，或作为通用酸以使O 5'离去基团质子化。在这里，我们报告的第一个理论检查的两种机制，使用量子力学（QM）/分子力学（MM），分子动力学（MD），和近攻击构象（NAC）技术的组合。我们的理论结果支持C75-酸机制，其被证明具有不利的起始几何形状（与晶体学数据一致），但与C75-碱机制相比具有显著较低的能垒。因此，HDV核酶中过渡态的化学细节可能与从结构研究中推断的那些有很大不同。
Two mechanisms were previously proposed for the hepatitis delta virus (HDV) ribozyme where an active-site cytosine residue (C75) either functioned as a general base to deprotonate the 2'-OH at the rupture site or as a general acid to protonate the O5' leaving group. Here, we reported the first theoretical examination of the two mechanisms using a combination of the quantum mechanics (QM)/molecular mechanics (MM), molecular dynamics (MD), and near-attack-conformation (NAC) techniques. Our theoretical results supported the C75-acid mechanism, which was demonstrated to have an unfavorable starting geometry (in agreement with the crystallographic data) but a significantly lower energy barrier as compared to the C75-base mechanism. Therefore, the chemical details of the transition state in the HDV ribozyme may dramatically differ from those inferred from the structural studies.