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I-Motif folding intermediates with zero-nucleotide loops are trapped by 2'-fluoroarabinocytidine via F···H and O···H hydrogen bonds.

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.

SUBMITTER: El-Khoury R

PROVIDER: S-EPMC9935537 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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i-Motif folding intermediates with zero-nucleotide loops are trapped by 2'-fluoroarabinocytidine via F···H and O···H hydrogen bonds.

El-Khoury Roberto R Macaluso Veronica V Hennecker Christopher C Mittermaier Anthony K AK Orozco Modesto M González Carlos C Garavís Miguel M Damha Masad J MJ

Communications chemistry 20230216 1

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<sub>5</sub> normally folds into a stable tetrameric i-motif in solution, we report that 2'-deoxy-2'-fluoroarabinocytidine (araF-C) ...[more]

PMID: 36797370

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Project description:In the present work, the conformational dynamics and folding pathways of i-motif DNA were studied in solution and in the gas-phase as a function of the solution pH conditions using circular dichroism (CD), photoacoustic calorimetry analysis (PAC), trapped ion mobility spectrometry-mass spectrometry (TIMS-MS), and molecular dynamics (MD). Solution studies showed at thermodynamic equilibrium the existence of a two-state folding mechanism, whereas during the pH = 7.0 → 4.5 transition a fast and slow phase (ΔHfast + ΔHslow = 43 ± 7 kcal mol-1) with a volume change associated with the formation of hemiprotonated cytosine base pairs and concomitant collapse of the i-motif oligonucleotide into a compact conformation were observed. TIMS-MS experiments showed that gas-phase, kinetically trapped i-motif DNA intermediates produced by nanoESI are preserved, with relative abundances depending on the solution pH conditions. In particular, a folded i-motif DNA structure was observed in nanoESI-TIMS-MS for low charge states in both positive and negative ion mode (e.g., z = ±3 to ±5) at low pH conditions. As solution pH increases, the cytosine neutralization leads to the loss of cytosine-cytosine+ (C·CH+) base pairing in the CCC strands and in those conditions we observe partially unfolded i-motif DNA conformations in nanoESI-TIMS-MS for higher charge states (e.g., z = -6 to -9). Collisional induced activation prior to TIMS-MS showed the existence of multiple local free energy minima, associated with the i-motif DNA unfolding at z = -6 charge state. For the first time, candidate gas-phase structures are proposed based on mobility measurements of the i-motif DNA unfolding pathway. Moreover, the inspection of partially unfolded i-motif DNA structures (z = -7 and z = -8 charge states) showed that the presence of inner cations may or may not induce conformational changes in the gas-phase. For example, incorporation of ammonium adducts does not lead to major conformational changes while sodium adducts may lead to the formation of sodium mediated bonds between two negatively charged sides inducing the stabilization towards more compact structures in new local, free energy minima in the gas-phase.

Dataset Information

I-Motif folding intermediates with zero-nucleotide loops are trapped by 2'-fluoroarabinocytidine via F···H and O···H hydrogen bonds.

Publications

i-Motif folding intermediates with zero-nucleotide loops are trapped by 2'-fluoroarabinocytidine via F···H and O···H hydrogen bonds.

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