i-Motif folding intermediates with zero-nucleotide loops are trapped by 2′-fluoroarabinocytidine via F···H and O···H hydrogen bonds
Title | i-Motif folding intermediates with zero-nucleotide loops are trapped by 2′-fluoroarabinocytidine via F···H and O···H hydrogen bonds |
Publication Type | Journal Article |
Year of Publication | 2023 |
Authors | El-Khoury, Roberto, Macaluso Veronica, Hennecker Christopher, Mittermaier Anthony K., Orozco Modesto, González Carlos, Garavís Miguel, and Damha Masad J. |
Journal | Communications Chemistry |
Volume | 6 |
Issue | 1 |
Pagination | 31 |
Date Published | 02/2023 |
ISBN Number | 2399-3669 |
Abstract | 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 TC5 normally folds into a stable tetrameric i-motif in solution, we report that 2′-deoxy-2′-fluoroarabinocytidine (araF-C) substitutions can prompt TC5 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. |
URL | https://doi.org/10.1038/s42004-023-00831-7 |
Short Title | Communications Chemistry |