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Cross-modulation of the pKa of nucleobases in a single-stranded hexameric-RNA due to tandem electrostatic nearest-neighbor interactions

Cross-modulation of the pKa of nucleobases in a single-stranded hexameric-RNA due to tandem electrostatic nearest-neighbor interactions

Acharya, P. ORCID: 0000-0003-2521-9968, Acharya, S., Cheruku, P., Amirkhanov, N. V., Foldesi, A. and Chattopadhyaya, J. (2003) Cross-modulation of the pKa of nucleobases in a single-stranded hexameric-RNA due to tandem electrostatic nearest-neighbor interactions. Journal of the American Chemical Society, 125 (33). pp. 9948-9961. ISSN 0002-7863 (Print), 1520-5126 (Online) (doi:https://doi.org/10.1021/ja034651h)

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Abstract

The pH titration studies (pH 6.7−12.1) in a series of dimeric, trimeric, tetrameric, pentameric, and hexameric oligo-RNA molecules [GpA (2a), GpC (3a), GpApC (5), GpA1pA2pC (6), GpA1pA2pA3pC (7), GpA1pA2pA3pA4pC (8)] have shown that the pKa of N1−H of 9-guaninyl could be measured not only from its own δH8G, but also from the aromatic marker protons of other constituent nucleobases. The relative chemical shift differences [Δδ(N-D)] between the protons in various nucleotide residues in the oligo-RNAs at the neutral (N) and deprotonated (D) states of the guanine moiety show that the generation of the 5‘-(9-guanylate ion) in oligo-RNAs 2−8 reduces the stability of the stacked helical RNA conformation owing to the destabilizing anion(G-)−π/dipole(Imδ-) interaction. This destabilizing effect in the deprotonated RNA is, however, opposed by the electrostatically attractive atom−πσ (major) as well as the anion(G-)−π/dipole(Pyδ+) (minor) interactions. Our studies have demonstrated that the electrostatically repulsive anion(G-)−π/dipole(Imδ-) interaction propagates from the first to the third nucleobase quite strongly in the oligo-RNAs 6−8, causing destacking of the helix, and then its effect is gradually reduced, although it is clearly NMR detectable along the RNA chain. Thus, such specific generation of a charge at a single nucleobase moiety allows us to explore the relative strength of stacking within a single-stranded helix. The pKa of 5‘-Gp residue from its own δH8G in the hexameric RNA 8 is found to be 9.76 ± 0.01; it, however, varies from 9.65 ± 0.01 to 10.5 ± 0.07 along the RNA chain as measured from the other marker protons (H2, H8, H5, and H6) of 9-adeninyl and 1-cytosinyl residues. This nucleobase-dependent modulation of pKas (ΔpKa ± 0.9) of 9-guaninyl obtained from other nucleobases in the hexameric RNA 8 represents a difference of ca. 5.1 kJ mol-1, which has been attributed to the variable strength of electrostatic interactions between the electron densities of the involved atoms in the offset stacked nucleobases as well as with that of the phosphates. The chemical implication of this variable pKa for guanin-9-yl deprotonation as obtained from all other marker protons of each nucleotide residue within a ssRNA molecule is that it enables us to experimentally understand the variation of the electronic microenvironment around each constituent nucleobase along the RNA chain in a stepwise manner with very high accuracy without having to make any assumption. This means that the pseudoaromaticity of neighboring 9-adeninyl and next-neighbor nucleobases within a polyanionic sugar−phosphate backbone of a ssRNA can vary from one case to another due to cross-modulation of an electronically coupled π system by a neighboring nucleobase. This modulation may depend on the sequence context, spatial proximity of the negatively charged phosphates, as well as whether the offset stacking is ON or OFF. The net outcome of this electrostatic interaction between the neighbors is creation of new sequence-dependent hybrid nucleobases in an oligo- or polynucleotide whose properties are unlike the monomeric counterpart, which may have considerable biological implications.

Item Type: Article
Uncontrolled Keywords: nucleobase, NMR, molecular mechanics, aromatic compounds
Subjects: Q Science > QD Chemistry
Faculty / Department / Research Group: Faculty of Engineering & Science
Faculty of Engineering & Science > Natural Resources Institute
Faculty of Engineering & Science > Natural Resources Institute > Food & Markets Department
Last Modified: 10 Jul 2020 13:16
Selected for GREAT 2016: None
Selected for GREAT 2017: None
Selected for GREAT 2018: None
Selected for GREAT 2019: None
Selected for REF2021: None
URI: http://gala.gre.ac.uk/id/eprint/28725

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