Department of Biophysics, Molecular Biology and Bioinformatics, University of Calcutta, 92, Acharya Prafulla Chandra Road, Kolkata, West Bengal, 700009, India.
Institute of Bioorganic Chemistry, Polish Academy of Sciences, Noskowskiego 12/14, 61-704, Poznan, Poland.
J Comput Aided Mol Des. 2022 Mar;36(3):205-224. doi: 10.1007/s10822-022-00447-4. Epub 2022 Mar 26.
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 (χ) 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 (χ) 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.
假尿嘧啶核苷是 RNA 中转录后修饰最丰富的一种。我们之前已经表明，无论是单独使用还是与修正的γ扭转参数（parmbsc0）结合使用，FF99 衍生的假尿嘧啶核苷及其一些天然衍生物的参数都无法复制其实验观察到的构象特征（Deb 等人在 J Chem Inf Model 54：1129-1142，2014 年；Deb 等人在 J Comput Chem 37：1576-1588，2016 年；Dutta 等人在 J Chem Inf Model 60：4995-5002，2020 年）。然而，应用推荐的 bsc0 修正不仅改善了γ扭转空间分布的描述，也改善了糖环构象分布的描述。在早期的研究中，我们检查了修正的糖苷扭转参数（χ）对 Ψ 及其衍生物的可转移性。我们注意到，尽管这些参数与 AMBER FF99 衍生参数和修正的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一致，但糖环构象分布仍然无法准确再现。在这里，我们报告了一组新的假尿嘧啶核苷、1-甲基假尿嘧啶核苷、3-甲基假尿嘧啶核苷和 2'-O-甲基假尿嘧啶核苷的部分原子电荷和糖苷扭转参数（χ），这些参数是基于与 NMR 数据最接近的糖苷扭转轮廓选择的，用于研究它们对构象分布的影响，使用 REMD 模拟在单个核苷水平上进行。我们还研究了水模型选择对这些修饰核苷构象特征的影响。我们的观察表明，当前修正的参数和部分原子电荷集更准确地描述了这些残基的糖环构象分布，选择合适的水模型对于准确描述它们的构象性质很重要。我们进一步通过研究在单链 RNA 寡核苷酸中用假尿嘧啶核苷替代尿嘧啶对其构象和水合特性的影响来验证修正参数集的有效性。
