Disagreement Between the Structure of the dTpT Thymine Pair Determined by NMR and Molecular Dynamics Simulations Using Amber 14 Force Fields.
Disagreement Between the Structure of the dTpT Thymine Pair Determined by NMR and Molecular Dynamics Simulations Using Amber 14 Force Fields.
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DOI：
10.1021/acs.jpcb.6b00191
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发表时间：
2016-02
期刊：
影响因子：
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通讯作者：
C. Nganou;S. Kennedy;D. McCamant
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文献类型：
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作者：
C. Nganou;S. Kennedy;D. McCamant
我们报告了使用核磁共振（NMR）光谱和分子动力学（MD）模拟使用AMBER ff14 SB和ff14 + ε/ε/ε OL 1 + χ OL 4力场对DNA的dTpT胸腺嘧啶对（胸苷酰（3' → 5'）胸苷）的预测结构之间的不一致。使用NOE偶联到胸腺嘧啶的H6和糖质子之间的J（HH）偶联来确定NMR结构。MD模拟使用副本交换方法在500 ns轨迹中产生收敛统计。NMR数据表明，这对胸腺嘧啶核苷酸都显示出B-DNA的反构象，而MD模拟预测了其中5 '-胸腺嘧啶翻转成顺式构象而3'-胸腺嘧啶处于反构象的结构。与B型反式结构相比，MD预测的5 '-胸腺嘧啶的顺式构象出现了糖苷角的180度翻转。5 '-胸腺嘧啶和3'-胸腺嘧啶之间糖折叠变形的差异进一步突出了5 '-和3'-末端令人惊讶的不同构象。虽然MD和NMR都表明脱氧核糖主要处于B型DNA典型的2 '-内构象，但MD模拟预测5'-糖的更扭曲的构象（2 '-内/1'-外）和3 '-糖的C3'的显著柔性。我们的结论是，目前的琥珀色力场不能准确地预测单链胸腺嘧啶的构象，与以前的工作调查单链DNA。
We report a disagreement between the predicted structures of the dTpT thymine pair (thymidylyl(3' → 5')thymidine) using nuclear magnetic resonance (NMR) spectroscopy and molecular dynamics (MD) simulations using the AMBER ff14SB and ff14 + ε/ζOL1 + χOL4 force fields for DNA. The NMR structure was determined using NOE couplings to thymine's H6 and J(HH) couplings between sugar protons. The MD simulation used replica exchange methods to produce converged statistics in a 500 ns trajectory. NMR data indicate that both thymine nucleotides in the pair display an anti conformation of B-DNA, while the MD simulations predict a structure in which the 5'-thymine is flipped into a syn conformation and the 3'-thymine is in an anti conformation. The syn conformation of the 5'-thymine predicted by MD appears by a ∼ 180-deg flip of the glycosidic angle in comparison to the B-form anti structure. Differences in the distortion of the sugar pucker between 5'-thymine and 3'-thymine further highlighted the surprisingly different conformation of the 5'- and 3'-ends. While both MD and NMR indicate the deoxyribose sugars to be primarily in the 2'-endo conformation typical of B-form DNA, the MD simulations predict a more twisted conformation (2'-endo/1'-exo) for the 5'-sugar and significant flexibility of C3' of the 3'-sugar. We conclude that the current AMBER force field does not accurately predict the conformation of single-stranded thymine, in agreement with previous work investigating single-stranded DNA.