Stacking Free Energies of All DNA and RNA Nucleoside Pairs and Dinucleoside-Monophosphates Computed Using Recently Revised AMBER Parameters and Compared with Experiment
Stacking Free Energies of All DNA and RNA Nucleoside Pairs and Dinucleoside-Monophosphates Computed Using Recently Revised AMBER Parameters and Compared with Experiment
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DOI：
10.1021/ct501170h
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发表时间：
2015-05-01
影响因子：
5.5
通讯作者：
Elcock, Adrian H.
中科院分区：
文献类型：
--
作者：
Brown, Reid F.;Andrews, Casey T.;Elcock, Adrian H.
我们报告了一系列的1 μ s长的显式溶剂分子动力学（MD）模拟的结果进行比较的自由能堆叠（Δ G（堆栈））的所有可能的组合的DNA和RNA核苷（NS）对和二核苷单磷酸（DNMP）。对于NS对和DNMP，我们表明，计算的堆叠自由能是在合理的定性协议与实验测量，并出现提供最密切的对应关系与实验数据之间尚未发现的计算研究;然而，在所有情况下，计算的堆叠自由能相对于实验数据过于有利。NS-对系统的比较表明，堆积相互作用在RNA和DNA系统中非常相似，除了当涉及胸腺嘧啶或尿嘧啶碱基时：胸腺嘧啶碱基的存在有利于堆积，相对于尿嘧啶碱基，堆积量为0.3 kcal/mol。一个例外是发现在自堆叠的胞苷，这被发现是显着更有利的DNA形式;堆叠事件期间采样的旋转方向的分析表明，这可能是由于更有利的糖糖相互作用在堆叠复合物的脱氧胞苷。DNMP系统的比较表明，堆积相互作用在RNA中比在DNA中更有利，再次除了当涉及胸腺嘧啶或尿嘧啶碱基时。最后，使用上一代的琥珀色力场进行额外的模拟，其中糖苷键旋转的描述小于最优产生计算的堆积自由能，与实验数据的一致性较差。总体而言，模拟提供了一个全面的视图堆叠热力学NS对和DNMP预测的最先进的MD力场。
We report the results of a series of 1- mu s-long explicit-solvent molecular dynamics (MD) simulations performed to compare the free energies of stacking (Delta G(stack)) of all possible combinations of DNA and RNA nucleoside (NS) pairs and dinucleoside-monophosphates (DNMPs). For both NS pairs and DNMPs, we show that the computed stacking free energies are in reasonable qualitative agreement with experimental measurements and appear to provide the closest correspondence with experimental data yet found among computational studies; in all cases, however, the computed stacking free energies are too favorable relative to experimental data. Comparisons of NS-pair systems indicate that stacking interactions are very similar in RNA and DNA systems except when a thymine or uracil base is involved: the presence of a thymine base favors stacking by similar to 0.3 kcal/mol relative to a uracil base. One exception is found in the self-stacking of cytidines, which are found to be significantly more favorable for the DNA form; an analysis of the rotational orientations sampled during stacking events suggests that this is likely to be due to more favorable sugarsugar interactions in stacked complexes of deoxycytidines. Comparisons of the DNMP systems indicate that stacking interactions are more favorable in RNA than in DNA except, again, when thymine or uracil bases are involved. Finally, additional simulations performed using a previous generation of the AMBER force fieldin which the description of glycosidic bond rotations was less than optimalproduce computed stacking free energies that are in poorer agreement with experimental data. Overall, the simulations provide a comprehensive view of stacking thermodynamics in NS pairs and in DNMPs as predicted by a state-of-the-art MD force field.