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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• 作者：Collins Nganou ; Scott D. Kennedy ; David W. McCamant
• 刊名：Journal of Physical Chemistry B
• 出版年：2016
• 出版时间：February 25, 2016
• 年：2016
• 卷：120
• 期：7
• 页码：1250-1258
• 全文大小：520K
• ISSN：1520-5207

文摘

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.