Free energy calculation of modified base-pair formation in explicit solvent: A predictive model
Free energy calculation of modified base-pair formation in explicit solvent: A predictive model
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DOI：
10.1261/rna.1734309
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发表时间：
2009-12-01
期刊：
影响因子：
4.5
通讯作者：
Agris, Paul F.
中科院分区：
文献类型：
--
作者：
Vendeix, Franck A. P.;Munoz, Antonio M.;Agris, Paul F.
RNA的成熟包括位点特异性转录后修饰，其显著促进RNA内和不同RNA之间的氢键形成，特别是在错配碱基对的形成中。因此，对修饰的核糖核苷5 '-单磷酸的碱基配对的几何形状和强度的理解，以前没有定义，适用于RNA结构和功能的研究和新RNA的设计。采用AMBER力场和分子动力学模拟方法计算了中性条件下水溶液中碱基对的几何构型和自由能。例如，观察到未修饰的尿苷以显著的稳定性结合尿苷和胞苷，但是核糖C1 '-C1'距离远短于（类似于8.9埃）典型的A型RNA螺旋所观察到的距离。相比之下，已知结合腺苷、摆动至鸟苷并与尿苷和胞苷形成错配碱基对的5-氧乙酸尿苷以与未修饰的尿苷相当的几何形状和能量结合腺苷和鸟苷。然而，5-氧乙酸尿苷碱基与尿苷和胞苷配对，其C1 '-C1'距离与A型螺旋的距离相当，类似于11埃，当H2O分子在两个碱基之间迁移并稳定氢键结合时。即使在形成规范的碱基对，中间结构与第二个能量最小值的瞬态H2O分子形成氢键之间的两个基地。因此，MDS是预测的影响修改，H2O分子干预碱基对几何形状的形成，和能量是重要的天然RNA的结构和功能。
The maturation of RNAs includes site-specific post-transcriptional modifications that contribute significantly to hydrogen bond formation within RNA and between different RNAs, especially in formation of mismatch base pairs. Thus, an understanding of the geometry and strength of the base-pairing of modified ribonucleoside 5'-monophosphates, previously not defined, is applicable to investigations of RNA structure and function and of the design of novel RNAs. The geometry and free energies of base-pairings were calculated in aqueous solution under neutral conditions with AMBER force fields and molecular dynamics simulations (MDSs). For example, unmodified uridines were observed to bind to uridine and cytidine with significant stability, but the ribose C1'-C1' distances were far short (similar to 8.9 angstrom) of distances observed for canonical A-form RNA helices. In contrast, 5-oxyacetic acid uridine, known to bind adenosine, wobble to guanosine, and form mismatch base pairs with uridine and cytidine, bound adenosine and guanosine with geometries and energies comparable to an unmodified uridine. However, the 5-oxyacetic acid uridine base paired to uridine and cytidine with a C1'-C1' distance comparable to that of an A-form helix, similar to 11 angstrom, when a H2O molecule migrated between and stably hydrogen bonded to both bases. Even in formation of canonical base pairs, intermediate structures with a second energy minimum consisted of transient H2O molecules forming hydrogen bonded bridges between the two bases. Thus, MDS is predictive of the effects of modifications, H2O molecule intervention in the formation of base-pair geometry, and energies that are important for native RNA structure and function.