Abstract：
Pseudouridine is one of the most abundant post-transcriptional modifications in RNA. We have previously shown that the FF99-derived parameters for pseudouridine and some of its naturally occurring derivatives in the AMBER distribution either alone or in combination with the revised γ torsion parameters (parmbsc0) failed to reproduce their conformational characteristics observed experimentally (Deb et al. in J Chem Inf Model 54:1129-1142, 2014; Deb et al. in J Comput Chem 37:1576-1588, 2016; Dutta et al. in J Chem Inf Model 60:4995-5002, 2020). However, the application of the recommended bsc0 correction did lead to an improvement in the description not only of the distribution in the γ torsional space but also of the sugar pucker distributions. In an earlier study, we examined the transferability of the revised glycosidic torsion parameters (χIDRP) for Ψ to its derivatives. We noticed that although these parameters in combination with the AMBER FF99-derived parameters and the revised γ torsional parameters resulted in conformational properties of these residues that were in better agreement with experimental observations, the sugar pucker distributions were still not reproduced accurately. Here we report a new set of partial atomic charges for pseudouridine, 1-methylpseudouridine, 3-methylpseudouridine and 2\'-O-methylpseudouridine and a new set of glycosidic torsional parameters (χND) based on chosen glycosidic torsional profiles that most closely corresponded to the NMR data for conformational propensities and studied their effect on the conformational distributions using REMD simulations at the individual nucleoside level. We have also studied the effect of the choice of water model on the conformational characteristics of these modified nucleosides. Our observations suggest that the current revised set of parameters and partial atomic charges describe the sugar pucker distributions for these residues more accurately and that the choice of a suitable water model is important for the accurate description of their conformational properties. We have further validated the revised sets of parameters by studying the effect of substitution of uridine with pseudouridine within single stranded RNA oligonucleotides on their conformational and hydration characteristics.
摘要：
假尿苷是RNA中最丰富的转录后修饰之一。我们先前已经表明，在AMBER分布中，假尿苷的FF99衍生参数及其一些天然存在的衍生物单独或与修正的γ扭转参数（parmbsc0）结合使用都无法重现实验观察到的构象特征（Deb等人。在JChemInf型号54：1129-1142，2014年；Deb等人。在JComputChem37：1576-1588，2016年；Dutta等人。在JChemInf模型60：4995-5002，2020年）。然而,推荐的bsc0校正的应用确实导致了不仅在γ扭转空间中的分布，而且在糖pucker分布的描述中得到了改进。在早期的一项研究中，我们检查了修正的糖苷扭转参数（χIDRP）对其衍生物的可转移性。我们注意到，尽管这些参数与AMBERFF99衍生参数和修订后的γ扭转参数相结合，导致这些残基的构象性质与实验观察结果更好地吻合，糖pucker分布仍未准确再现。在这里，我们报告了一组新的伪尿苷部分原子电荷，1-甲基假尿苷,3-甲基假尿苷和2'-O-甲基假尿苷以及一组新的糖苷扭转参数（χND），这些参数基于所选择的糖苷扭转曲线，这些曲线与构象倾向的NMR数据最接近，并研究了它们对构象分布的影响使用REMD模拟在单个核苷水平上。我们还研讨了水模子的选择对这些改性核苷构象特征的影响。我们的观察结果表明，当前修订后的参数集和部分原子电荷更准确地描述了这些残基的糖pucker分布，并且选择合适的水模型对于准确描述其构象特性很重要。我们通过研究在单链RNA寡核苷酸中用假尿苷取代尿苷对其构象和水合特性的影响，进一步验证了修改后的参数集。
