Optimization of an AMBER Force Field for the Artificial Nucleic Acid, LNA, and Benchmarking with NMR of L(CAAU)
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- 作者：David E. Condon ; Ilyas Yildirim ; Scott D. Kennedy ; Brendan C. Mort ; Ryszard Kierzek ; Douglas H. Turner
- 刊名：Journal of Physical Chemistry B
- 出版年：2014
- 出版时间：February 6, 2014
- 年：2014
- 卷：118
- 期：5
- 页码：1216-1228
- 全文大小：620K
- ISSN：1520-5207
文摘
Locked Nucleic Acids (LNAs) are RNA analogues with an O2鈥?C4鈥?methylene bridge which locks the sugar into a C3鈥?endo conformation. This enhances hybridization to DNA and RNA, making LNAs useful in microarrays and potential therapeutics. Here, the LNA, L(CAAU), provides a simplified benchmark for testing the ability of molecular dynamics (MD) to approximate nucleic acid properties. LNA 蠂 torsions and partial charges were parametrized to create AMBER parm99_LNA. The revisions were tested by comparing MD predictions with AMBER parm99 and parm99_LNA against a 200 ms NOESY NMR spectrum of L(CAAU). NMR indicates an A-Form equilibrium ensemble. In 3000 ns simulations starting with an A-form structure, parm99_LNA and parm99 provide 66% and 35% agreement, respectively, with NMR NOE volumes and 3J-couplings. In simulations of L(CAAU) starting with all 蠂 torsions in a syn conformation, only parm99_LNA is able to repair the structure. This implies methods for parametrizing force fields for nucleic acid mimics can reasonably approximate key interactions and that parm99_LNA will improve reliability of MD studies for systems with LNA. A method for approximating 蠂 population distribution on the basis of base to sugar NOEs is also introduced.