Optimization of an AMBER force field for the artificial nucleic acid, LNA, and benchmarking with NMR of L(CAAU).
Optimization of an AMBER force field for the artificial nucleic acid, LNA, and benchmarking with NMR of L(CAAU).
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DOI：
10.1021/jp408909t
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发表时间：
2014-02-06
期刊：
影响因子：
--
通讯作者：
Turner DH
中科院分区：
文献类型：
--
作者：
Condon DE;Yildirim I;Kennedy SD;Mort BC;Kierzek R;Turner DH
锁定核酸(LNAs)是具有O2‘-C4’亚甲基桥的RNA类似物，它将糖锁定为C3‘-endo构象。这增强了与DNA和RNA的杂交，使LNAs在微阵列和潜在的治疗中有用。在这里，LNA，L(CAAU)，为测试分子动力学(MD)近似核酸性质的能力提供了一个简化的基准。LNA的χ扭转和部分电荷被参数化为琥珀参数99_LNA。通过将MD预测与Amber parm99和parm99_LNA与L(CAAU)的200ms NOESY核磁共振谱进行比较，对修订进行了验证。核磁共振显示为A型平衡系综。在3000 ns的A-型结构模拟中，parm99_lna和parm99分别与核磁共振NOE体积和3J-偶联的一致性为66%和35%。在对L(CAAU)的模拟中，从一个SYN构象中的所有χ扭转开始，只有Parm99LNA能够修复该结构。这意味着，用于模拟核酸的力场的参数化方法可以合理地近似关键相互作用，并且parm99_LNA将提高具有LNA的体系的MD研究的可靠性。文中还介绍了一种基于碱基的χ种群分布逼近方法。
Locked Nucleic Acids (LNAs) are RNA analogues with an O2′-C4′ methylene bridge which locks the sugar into a C3′-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 χ 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 χ 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 χ population distribution on the basis of base to sugar NOEs is also introduced.
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