Influence of 5-Halogenation on the Base-Pairing Energies of Protonated Cytidine Nucleoside Analogue Base Pairs: Implications for the Stabilities of Synthetic<i>i</i>-Motif Structures for DNA Nanotechnology Applications

Rodgers, M. T.; Seidu, Yakubu S.; Israel, E

doi:10.1021/jasms.2c00137

Cited by 1 publication

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References 96 publications

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“…The fragmentation behavior observed here is consistent with previous studies of protonated cytosine nucleobase and cytidine nucleoside analogues and their base pairs previously examined using TCID [35][36][37][38][40][41][42]76 and IRMPD 77−82 techniques.…”

Section: Cross Sections For Collision-induced Dissociationsupporting

confidence: 90%

“…The growing appreciation of the roles that noncanonical nucleic acid structures play in health, disease, and aging has thus made it of paramount importance to also elucidate the impacts of nucleoside modifications of noncanonical DNA and RNA structures such as the i -motif. Our previous studies of protonated cytidine nucleoside analogue base pairs, models for the core stabilizing interactions of i -motifs, have established that 5-modifications of the cytosine residues alter the strength of base pairing. , Further, the influence of 5-modifications on the base pairing depend upon the nature/identity of both the 5- and 2′-substituents. 5-Methylation strengthens base pairing in the protonated cytidine DNA and RNA base pairs .…”

Section: Discussionmentioning

confidence: 99%

“…Trends among the 5halogenated systems clearly establish the importance of nucleoside polarizability on the strength of base pairing. 42 2. 5-Methylation of the cytosine bases of the (Cyd)H + (Cyd) base pair also strengthens the base-pairing interaction; however, the increase in the BPE is much smaller, only 3.9 ± 6.5 kJ/mol (measured) and 3.4−6.7 kJ/mol (computed).…”

Section: Electrostatic Potential Maps Of (Xcyd)h + (Xcyd) Basementioning

confidence: 99%

“…41 In contrast, 5halogenation was found to strengthen the base-pairing interactions of the DNA base pairs, but generally weakens the base-pairing interactions of the RNA base pairs. 42 Trends in the base-pairing energies (BPEs) as a function of the 5halogen substituent and 2′-substituents indicate that both the dipole and polarizability of the nucleoside influence the base pairing.…”

Section: ■ Introductionmentioning

confidence: 99%

“…The influence of 2′modifications on the structure and base-pairing interactions is elucidated by comparing present results with findings for the canonical DNA and RNA protonated cytidine nucleoside base pairs and their 5-methylated and 5-fluorinated analogues. 41,42 A detailed understanding of the effects of 5-and 2′modifications on the stability of i-motif conformations is important to the design and development of novel nucleic acid structures with high specificity and enhanced functionality for biomedical and nanotechnological applications.…”

Section: ■ Introductionmentioning

confidence: 99%

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Influence of 2′-Modifications (O-Methylation, Fluorination, and Stereochemical Inversion) on the Base Pairing Energies of Protonated Cytidine Nucleoside Analogue Base Pairs: Implications for the Stabilities ofi-Motif Structures

Rodgers

Seidu

Israel

2023

J. Am. Soc. Mass Spectrom.

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Naturally occurring and chemically engineered modifications are among the most powerful strategies explored for fine-tuning the conformational characteristics and intrinsic stability of nucleic acids topologies. Modifications at the 2′-position of the ribose or 2′-deoxyribose moieties differentiate nucleic acid structures and have a significant impact on their electronic properties and basepairing interactions. 2′-O-Methylation, a common post-transcriptional modification of tRNA, is directly involved in modulating specific anticodon−codon base-pairing interactions. 2′-Fluorinated and arabino nucleosides possess novel and beneficial medicinal properties and find use as therapeutics for treating viral diseases and cancer. However, the potential to deploy 2′-modified cytidine chemistries for tuning i-motif stability is largely unknown. To address this knowledge gap, the effects of 2′-modifications including O-methylation, fluorination, and stereochemical inversion on the base-pairing interactions of protonated cytidine nucleoside analogue base pairs, the core stabilizing interactions of i-motif structures, are examined using complementary threshold collision-induced dissociation techniques and computational methods. The 2′-modified cytidine nucleoside analogues investigated here include 2′-O-methylcytidine, 2′-fluoro-2′-deoxycytidine, arabinofuranosylcytosine, 2′-fluoroarabinofuranosylcytosine, and 2′,2′-difluoro-2′-deoxycytidine. All five 2′-modifications examined here are found to enhance the basepairing interactions relative to the canonical DNA and RNA cytidine nucleosides with the greatest enhancements arising from 2′-Omethylation and 2′,2′-difluorination, suggesting that these modifications should well be tolerated in the narrow grooves of i-motif conformations.

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