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The Effect of 2′F-RNA on I-Motif Structure and Stability

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Title: The Effect of 2′F-RNA on I-Motif Structure and Stability
Authors: Cristina Ugedo, Arnau Domínguez, Irene Gómez-Pinto, Ramon Eritja, Carlos González, Anna Aviñó
Source: Molecules, Vol 30, Iss 17, p 3561 (2025)
Publisher Information: MDPI AG, 2025.
Publication Year: 2025
Collection: LCC:Organic chemistry
Subject Terms: i-motif, NMR, non-canonical nucleic acids, XNA, fluorine substitution, Organic chemistry, QD241-441
Description: I-motifs are non-canonical, cytosine-rich DNA structures stabilized by hemiprotonated C•C+ base pairs, whose formation is highly pH-dependent. While certain chemical modifications can enhance i-motif stability, modifications at the sugar moiety often disrupt essential inter-strand contacts. In this study, we examine the structural and thermodynamic impact of incorporating 2′-fluoro-ribocytidine (2′F-riboC) into i-motif-forming sequences derived from d(TCCCCC). Using a combination of UV, 1H NMR, and 19F NMR spectroscopy, we demonstrate that full substitution with 2′F-riboC strongly destabilizes i-motif, whereas partial substitutions (one or two substitutions per strand) support well-folded structures at acidic pH (pH 5). High-resolution NMR structures reveal well-defined i-motif architectures with conserved C•C+ pairing and characteristic interstrand NOEs. Sugar conformational analysis reveals a predominant North pucker for cytosines, which directs the fluorine substituent toward the minor groove of the i-motif. 19F NMR further confirms slow exchange between folded and unfolded species, enabling the simultaneous detection of both under identical experimental conditions and, consequently, highlighting the utility of fluorine at the 2′ sugar position as a spectroscopic probe. These findings provide insights into fluorine-mediated modulation of i-motif stability and further extend the utility of 19F NMR in nucleic acid research.
Document Type: article
File Description: electronic resource
Language: English
ISSN: 1420-3049
Relation: https://www.mdpi.com/1420-3049/30/17/3561; https://doaj.org/toc/1420-3049
DOI: 10.3390/molecules30173561
Access URL: https://doaj.org/article/b1036bd1512e4b4a80db0ea8054df92c
Accession Number: edsdoj.b1036bd1512e4b4a80db0ea8054df92c
Database: Directory of Open Access Journals
Description
Abstract:I-motifs are non-canonical, cytosine-rich DNA structures stabilized by hemiprotonated C•C+ base pairs, whose formation is highly pH-dependent. While certain chemical modifications can enhance i-motif stability, modifications at the sugar moiety often disrupt essential inter-strand contacts. In this study, we examine the structural and thermodynamic impact of incorporating 2′-fluoro-ribocytidine (2′F-riboC) into i-motif-forming sequences derived from d(TCCCCC). Using a combination of UV, 1H NMR, and 19F NMR spectroscopy, we demonstrate that full substitution with 2′F-riboC strongly destabilizes i-motif, whereas partial substitutions (one or two substitutions per strand) support well-folded structures at acidic pH (pH 5). High-resolution NMR structures reveal well-defined i-motif architectures with conserved C•C+ pairing and characteristic interstrand NOEs. Sugar conformational analysis reveals a predominant North pucker for cytosines, which directs the fluorine substituent toward the minor groove of the i-motif. 19F NMR further confirms slow exchange between folded and unfolded species, enabling the simultaneous detection of both under identical experimental conditions and, consequently, highlighting the utility of fluorine at the 2′ sugar position as a spectroscopic probe. These findings provide insights into fluorine-mediated modulation of i-motif stability and further extend the utility of 19F NMR in nucleic acid research.
ISSN:14203049
DOI:10.3390/molecules30173561