Microsecond-Scale MD Simulations of HIV-1 DIS Kissing-Loop Complexes Predict Bulged-In Conformation of the Bulged Bases and Reveal Interesting Differences between Available Variants of the AMBER RNA Force Fields
Microsecond-Scale MD Simulations of HIV-1 DIS Kissing-Loop Complexes Predict Bulged-In Conformation of the Bulged Bases and Reveal Interesting Differences between Available Variants of the AMBER RNA Force Fields
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DOI：
10.1021/acs.jpcb.5b08876
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发表时间：
2015-12-10
影响因子：
3.3
通讯作者：
Sponer, Jiri
中科院分区：
文献类型：
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作者：
Havrila, Marek;Zgarbova, Marie;Sponer, Jiri
我们报道了一组广泛的明确溶剂分子动力学（MD）模拟（类似于25 μ s的累积模拟时间）的RNA接吻环复合物的HIV-1病毒起始二聚化位点。尽管通过x射线、核磁共振和MD技术进行了许多结构研究，但接吻复合物中凸起嘌呤的位置尚未得到明确的解决。x射线结构一致显示未配对碱基的凸起位置，而一些核磁共振研究显示凸起构象。然而，核磁共振研究在碱基的确切方向上相互矛盾。早期的模拟研究预测了凸出构象；然而，这一发现可能因模拟时间较短而存在偏差。我们的微秒模拟显示，所有未配对的碱基都最好停留在接吻环复合物的内部。MD结果在现有实验数据的背景下进行了讨论，我们认为这两种构象都具有生物化学相关性。我们还表明，MD对这种RNA系统提供了相当令人满意的描述，与最近报道的较小系统（如四核苷酸和四环）的RNA力场不令人满意的表现形成对比。我们用这样一个事实来解释这一点，即接吻复合体主要是由一个广泛的沃森-克里克相互作用网络稳定的，这些相互作用是由力场很好地描述的。我们测试了几组不同的水/离子参数，但它们都得出了一致的结果。然而，我们证明了最近提出的对Cornell等人力场的van der Wools相互作用的修改，通过失去稳定螺旋间结和过量氢键相互作用的关键堆叠相互作用，恶化了对接吻复合物的描述。
We report an extensive set of explicit solvent molecular dynamics (MD) simulations (similar to 25 mu s of accumulated simulation time) of the RNA kissing-loop complex of the HIV-1 virus initiation dimerization site. Despite many structural investigations by X-ray, NMR, and MD techniques, the position of the bulged purines of the kissing complex has not been unambiguously resolved. The X-ray structures consistently show bulged-out positions of the unpaired bases, while several NMR studies show bulged-in conformations. The NMR studies are, however, mutually inconsistent regarding the exact orientations of the bases. The earlier simulation studies predicted the bulged-out conformation; however, this finding could have been biased by the short simulation time scales. Our microsecond-long simulations reveal that all unpaired bases of the kissing-loop complex stay preferably in the interior of the kissing-loop complex. The MD results are discussed in the context of the available experimental data and we suggest that both conformations are biochemically relevant. We also show that MD provides a quite satisfactory description of this RNA system, contrasting recent reports of unsatisfactory performance of the RNA force fields for smaller systems such as tetranucleotides and tetraloops. We explain this by the fact that the kissing complex is primarily stabilized by an extensive network of Watson Crick interactions which are rather well described by the force fields. We tested several different sets of water/ion parameters but they all lead to consistent results. However, we demonstrate that a recently suggested modification of van der Wools interactions of the Cornell et al. force field deteriorates the description of the kissing complex by the loss of key stacking interactions stabilizing the interhelical junction and excessive hydrogen-bonding interactions.