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Publication Abstract from PubMed

G-quadruplex and i-motif nucleic acid structures are believed to fold through kinetic partitioning mechanisms. Such mechanisms explain the structural heterogeneity of G-quadruplex metastable intermediates which have been extensively reported. On the other hand, i-motif folding is regarded as predictable, and research on alternative i-motif folds is limited. While TC(5) normally folds into a stable tetrameric i-motif in solution, we report that 2'-deoxy-2'-fluoroarabinocytidine (araF-C) substitutions can prompt TC(5) to form an off-pathway and kinetically-trapped dimeric i-motif, thereby expanding the scope of i-motif folding landscapes. This i-motif is formed by two strands, associated head-to-head, and featuring zero-nucleotide loops which have not been previously observed. Through spectroscopic and computational analyses, we also establish that the dimeric i-motif is stabilized by fluorine and non-fluorine hydrogen bonds, thereby explaining the superlative stability of araF-C modified i-motifs. Comparative experimental findings suggest that the strength of these interactions depends on the flexible sugar pucker adopted by the araF-C residue. Overall, the findings reported here provide a new role for i-motifs in nanotechnology and also pose the question of whether unprecedented i-motif folds may exist in vivo.

i-Motif folding intermediates with zero-nucleotide loops are trapped by 2'-fluoroarabinocytidine via F...H and O...H hydrogen bonds.,El-Khoury R, Macaluso V, Hennecker C, Mittermaier AK, Orozco M, Gonzalez C, Garavis M, Damha MJ Commun Chem. 2023 Feb 16;6(1):31. doi: 10.1038/s42004-023-00831-7. PMID:36797370^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.