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Base-Pairing Behavior of a Carbocyclic Janus-AT Nucleoside Analogue Capable of Recognizing A and T within a DNA Duplex

Authors

  • Dr. Eric Largy,

    1. Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, BC V6T 1Z1 (Canada)
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    • These authors contributed equally to this work.

  • Wenbo Liu,

    1. Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, BC V6T 1Z1 (Canada)
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    • These authors contributed equally to this work.

  • Abid Hasan,

    1. Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, BC V6T 1Z1 (Canada)
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  • Prof. David M. Perrin

    Corresponding author
    1. Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, BC V6T 1Z1 (Canada)
    • Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, BC V6T 1Z1 (Canada)

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Abstract

Janus-type nucleosides are heterocycles with two faces, each of which is designed to complement the H-bonding interactions of natural nucleosides comprising a canonical Watson–Crick base pair. By intercepting all of the hydrogen bonds contained within the base pair, oligomeric Janus nucleosides are expected to achieve sequence-specific DNA recognition through the formation of J-loops that will be more stable than D-loops, which simply replaces one base-pair with another. Herein, we report the synthesis of a novel Janus-AT nucleoside analogue, JAT, affixed on a carbocyclic analogue of deoxyribose that was converted to the corresponding phosphoramidite. A single JAT was successfully incorporated into a DNA strand by solid phase for targeting both A and T bases, and characterized through biophysical and computational methods. Experimental UV-melting and circular dichroism data demonstrated that within the context of a standard duplex, JAT associates preferentially with T over A, and much more poorly with C and G. Density functional theory calculations confirm that the JAT structure is well suited to associate only with A and T thereby highlighting the importance of the electronic structure in terms of H-bonding. Finally, molecular dynamics simulations validated the observation that JAT can substitute more effectively as an A-analogue than as a T-analogue without substantial distortion of the B-helix. Overall, this new Janus nucleotide is a promising tool for the targeting of A–T base pairs in DNA, and will lead to the development of oligo-Janus-nucleotide strands for sequence-specific DNA recognition.

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