Calculations of pK_a Values for a Series of Naturally Occurring Modified Nucleobases

Abstract

Modified nucleobases are found in functionally important regions of RNA and are often responsible for essential structural roles. Many of these nucleobase modifications are dynamically regulated in nature, with each modification having a different biological role in RNA. Despite the high abundance of modifications, many of their characteristics are still poorly understood. One important property of a nucleobase is its pK a value, which has been widely studied for unmodified nucleobases, but not for the modified versions. In this study, the pK a values of modified nucleobases were determined by performing ab initio quantum mechanical calculations using a B3LYP density functional with the 6-31+G­(d,p) basis set and a combination of implicit–explicit solvation systems. This method, which was previously employed to determine the pK a values of unmodified nucleobases, is applicable to a variety of modified nucleobases. Comparisons of the pK a values of modified nucleobases give insight into their structural and energetic impacts within nucleic acids.

Protein-Based Virtual Screening Tools Applied for RNA–Ligand Docking Identify New Binders of the preQ1-Riboswitch

“…While we identified the importance of the correct selection of ligand protomers and tautomers (Figure A–C), similarly rare protomers and tautomers of RNA might also play a role for ligand recognition in specific cases. , Additionally, it is to be taken into account that besides the four nucleobases, over 170 RNA modifications are reported, − which occur in biological systems and require individual tautomer and protomer considerations and potentially parameterization …”

“…125,126 Additionally, it is to be taken into account that besides the four nucleobases, over 170 RNA modifications are reported, 127−129 which occur in biological systems and require individual tautomer and protomer considerations and potentially parameterization. 130 Another aspect worth consideration is the functional role of ions. While a diffuse ion atmosphere masks the negative charge of the RNA backbone, 131 especially free and metabolite-bound Mg 2+ ions play an important role in RNA folding, stabilization, and protection from degradation.…”

DNA with Purine–Purine Base Pairs: Size and Position of Isoguanine and 8-Aza-7-deazaisoguanine Clickable Residues Control the Molecular Recognition of Guanine and 5-Aza-7-deazaguanine

“…This affects the base pairing capabilities of nucleobases in nucleic acids, for example, the formation of Watson–Crick base pairs in double-stranded DNA. To this end, the role of p K values of nucleobases has been studied with respect to the origin of chemical evolution, and the robustness of base pairs was correlated to the p K value difference (Δp K ) of acceptor and donor sites of nucleobases . Accordingly, the p K values of the 8-substituted isoguanine nucleosides 1a–c were determined by spectrophotometric titration (pH 2–13.5) at 220–450 nm (Figures S3 and S4, Supporting Information) and were compared to those of 8-aza-7-deazaisoguanine nucleosides 2a–c and complementary nucleosides dG and dZ.…”

Three's a crowd – stabilisation, structure, and applications of DNA triplexes

“…55,66 In recent calculations, it was demonstrated that the methylation of C also shis the pKa from 4.6 (for cytidine) to 4.9. 68 The 2 0 -O-methylpseudoisocytidine (Fig. 9b) promotes the formation of triplexes in a neutral environment in a TFO that will recognize GC-tracts, exemplied using poly(GC).…”