There are only four derivatives of pseudouridine (Ψ) that are known to occur naturally in RNA as post-transcriptional modifications. We have studied the conformational consequences of pseudouridylation and further modifications using replica exchange molecular dynamics simulations at the nucleoside level, and the simulated conformational preferences were compared with the available experimental (NMR) data. We found that the existing AMBER FF99-derived parameters for these nucleosides did not reproduce the observed experimental features and while the recommended bsc0 correction could be combined with these parameters leading to an improvement in the description of sugar pucker distributions, the χOL3 correction could not be applied to these nucleosides as such because of base isomerization. On the other hand, the revised χ torsion parameters (χIDRP) for Ψ developed earlier by us (DebI. Deb, I. J. Comput. Chem.20163715761588) in combination with the AMBER provided parameters and the revised γ torsion parameters generated conformational distributions, which generally were in better agreement with the experimental data. A significant shift of the distribution of base orientation toward the syn conformation was observed with our revised parameter sets compared to the large excess of anti conformation predicted by the FF99 parameters. Overall, our observations indicated that our revised set of parameters (χIDRP) for Ψ were also able to generate conformational distributions for all of the derivatives of Ψ in better agreement with the experimental data.
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 IDRP ) 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 ND ) 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. Supplementary Information The online version contains supplementary material available at 10.1007/s10822-022-00447-4.
Pseudouridine (Ψ) is one of the most common post-transcriptional modifications in RNA and has been known to play significant roles in several crucial biological processes. The N1-methyl derivative of pseudouridine i.e N1-methylpseudouridine has also been reported to be important for the stability and function of RNA. Several studies suggest the importance of pseudouridine and N1-methylpseudouridine in mRNA therapeutics. The critical contribution of pseudouridine, especially that of its N1-methyl derivative in the efficiency of the COVID-19 mRNA vaccines, suggests the requirement to better understand the role of these modifications in the structure, stability and function of RNA. In the present study, we have investigated the consequences of the presence of these modifications in the stability of RNA duplex structures by analyzing different structural properties, hydration characteristics and energetics of these duplexes. We have previously studied the structural and thermodynamic properties of RNA duplexes with an internal Ψ-A pair and reported the stabilizing effect of Ψ over U (Deb, I. et al. Sci Rep 9, 16278 (2019)). Here, we have extended our work to understand the properties of RNA duplexes with an internal m1Ψ-A pair and also theoretically demonstrate the effect of substituting internal U-G, U-U and U-C mismatches with the Ψ-G, Ψ-U and Ψ-C mismatches and also with the m1Ψ-G, m1Ψ-U and m1Ψ-C mismatches respectively, within dsRNA. Our results indicate the context-dependent stabilization of base stacking interactions by N1-methylpseudouridine compared to uridine and pseudouridine, presumably resulting from the increased molecular polarizability due to the presence of the methyl group.
Pseudouridine is the most abundant post-transcriptional modification 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 I, et al. J. Chem. Inf. Model. 2014, 54 (4):1129–1142; Deb I, et al. J. Comput. Chem., 2016, 37:1576−1588; Dutta N, et al. J. Chem. Inf. Model. 2020, 60 (10):4995–5002). 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 glycosidic torsional parameters (𝛘ND) based on glycosidic torsional profiles that correspond to known conformational propensities and a new set of partial atomic charges for pseudouridine, 1-methylpseudouridine, 3-methylpseudouridine and 2′-O-methylpseudouridine 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.
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