Abstract
Incorporation of pseudoisocytidine (psC), a neutral analogue of protonated cytidine, in i-motifs has been studied by spectroscopic methods. Our results show that neutral psC:C base pairs can stabilize i-motifs at neutral pH, but the stabilization only occurs when psC:C base pairs are located at the ends of intercalated C:C+ stacks. When psC occupies central positions, the resulting i-motifs are only observed at low pH and psC:C+ or psC:psC+ hemiprotonated base pairs are formed instead of their neutral analogs. Overall, our results suggest that positively charged base pairs are necessary to stabilize this non-canonical DNA structure.
Highlights
I-motifs are quadruplex structures formed by the intercalation of hemiprotonated C:C+ base pairs
The appropriate pseudoisocytosine tautomer can hybridize with cytosine forming a neutral psC:C base pair
We have shown that the effect of replacing cytidine residues by psC strongly depends on the location of the cytidine residues
Summary
I-motifs are quadruplex structures formed by the intercalation of hemiprotonated C:C+ base pairs They are usually found in repetitive C-rich sequences and, as protonation of cytosines is required, are more stable at acidic pH1, 2. Pseudoisocytidine is an isostere of cytidine with lower pKa values[26] (3.79 (N1) and 3.69 (N3)) that exhibits a tautomeric equilibrium providing an additional hydrogen-bond donor at the N3 position (see Fig. 1A) This modification has been used in previous studies to stabilize parallel triplexes by substituting protonated cytidine residues in C+:G:C triplets[27,28,29,30]. The appropriate pseudoisocytosine tautomer can hybridize with cytosine forming a neutral psC:C base pair (see Fig. 1B) This pair is isomorphic to the hemiprotonated C:C+ base pair and may yield more stable i-motifs at neutral conditions.
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