DNA i-Motifs With Guanidino-i-Clamp Residues: The Counterplay Between Kinetics and Thermodynamics and Implications for the Design of pH Sensors

Vladimir B. Tsvetkov, Timofei S. Zatsepin, Anton V. Turaev, Valentina M. Farzan, Galina E. Pozmogova, Andrey V. Aralov, Anna M. Varizhuk

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    3 Citations (Scopus)


    I-motif structures, adopted by cytosine-rich DNA strands, have attracted considerable interest as possible regulatory elements in genomes. Applied science exploits the advantages of i-motif stabilization under acidic conditions: i-motif-based pH sensors and other biocompatible nanodevices are being developed. Two key characteristics of i-motifs as core elements of nanodevices, i.e., their stability under physiological conditions and folding/unfolding rates, still need to be improved. We have previously reported a phenoxazine derivative (i-clamp) that enhances the thermal stability of the i-motif and shifts the pH transition point closer to physiological values. Here, we performed i-clamp guanidinylation to further explore the prospects of clamp-like modifications in i-motif fine-tuning. Based on molecular modeling data, we concluded that clamp guanidinylation facilitated interstrand interactions in an i-motif core and ultimately stabilized the i-motif structure. We tested the effects of guanidino-i-clamp insertions on the thermal stabilities of genomic and model i-motifs. We also investigated the folding/unfolding kinetics of native and modified i-motifs under moderate, physiologically relevant pH alterations. We demonstrated fast folding/unfolding of native genomic and model i-motifs in response to pH stimuli. This finding supports the concept of i-motifs as possible genomic regulatory elements and encourages the future design of rapid-response pH probes based on such structures. Incorporation of guanidino-i-clamp residues at/near the 5′-terminus of i-motifs dramatically decreased the apparent unfolding rates and increased the thermal stabilities of the structures. This counterplay between the effects of modifications on i-motif stability and their effects on kinetics should be taken into account in the design of pH sensors.

    Original languageEnglish
    Pages (from-to)527-536
    Number of pages10
    JournalComputational and Structural Biotechnology Journal
    Publication statusPublished - 2019


    • DNA secondary structure
    • I-motif
    • Kinetics
    • pH sensor
    • Phenoxazine derivative
    • Thermal stability


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