Journal
ORGANIC & BIOMOLECULAR CHEMISTRY
Volume 16, Issue 24, Pages 4537-4546Publisher
ROYAL SOC CHEMISTRY
DOI: 10.1039/c8ob01198b
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Funding
- NCI Cancer Center Support Grant [P30 CA042014]
- National Science Foundation [CHE-1507813]
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Previously our laboratory identified that poly-2-deoxycytidine (dC(n)) strands of DNA with lengths greater than 12 nucleotides could adopt i-motif folds, while the pH-dependent stabilities follow a 4n - 1 repeat pattern with respect to chain length (J. Am. Chem. Soc., 2017, 139, 4682-4689). Herein, model i-motif folds in which loop configurations were forced by judiciously mutating dC to non-dC nucleotides allowed a structural model to be proposed to address this phenomenon. The model was developed by systematically studying two i-motifs with either an even or odd number of d(CC)(+) hemiprotonated base pairs in the core. First, a trend in the pH-dependent stability vs. loop nucleotide identity was observed: dC > dT approximate to dU >> dA approximate to dG. Next, loops comprised of dT nucleotides in the two different core base pair configurations were studied while systematically changing the loop lengths. We found that an i-motif with an even number of base pairs in the core with a single nucleotide in each of the three loops was the most stable, as well as an i-motif with an odd number of core base pairs having one nucleotide in the two exterior loops and three nucleotides in the central loop. A systematic increase in the central loop from 1-4 nucleotides for an odd number of base pairs in the i-motif core reproduced the 4n - 1 repeat pattern observed in the poly-dC(n) strands. Additional loop configurations were studied to further support the model. The results are discussed with respect to their biological relevance.
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