Data-informed reparameterization of modified RNA and the effect of explicit water models: Application to pseudouridine and derivatives

21 February 2022, Version 2
This content is a preprint and has not undergone peer review at the time of posting.

Abstract

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, 37:1576βˆ’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 (π›˜IDRP) for Ξ¨ 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 2β€²-O-methylpseudouridine and a new set of glycosidic torsional parameters (π›˜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.

Keywords

RNA modification
pseudouridine
glycosidic torsion
conformational characteristics
hydration pattern

Supplementary materials

Title
Description
Actions
Title
Data-informed reparameterization of modified RNA and the effect of explicit water models: Application to pseudouridine and derivatives
Description
Supporting information
Actions

Comments

Comments are not moderated before they are posted, but they can be removed by the site moderators if they are found to be in contravention of our Commenting Policy [opens in a new tab] - please read this policy before you post. Comments should be used for scholarly discussion of the content in question. You can find more information about how to use the commenting feature here [opens in a new tab] .
This site is protected by reCAPTCHA and the Google Privacy Policy [opens in a new tab] and Terms of Service [opens in a new tab] apply.