title: Base-pairing behavior of a carbocyclic Janus-AT nucleoside analogue capable of recognizing A and T within a DNA duplex.
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.
authors.affiliation: Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, BC V6T 1Z1 (Canada).
authors.forename: Eric
authors.initials: E
authors.lastname: Largy
authors.forename: Wenbo
authors.initials: W
authors.lastname: Liu
authors.forename: Abid
authors.initials: A
authors.lastname: Hasan
authors.forename: David M
authors.initials: DM
authors.lastname: Perrin
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000378:metabolism; D020029:Base Pairing; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D006860:Hydrogen Bonding; D056004:Molecular Dynamics Simulation; D009690:Nucleic Acid Conformation; D009691:Nucleic Acid Denaturation; D013816:Thermodynamics; D013941:Thymine / Q000031:analogs & derivatives* / Q000378:metabolism; D014466:Ultraviolet Rays
chemical_list: D004247:DNA; D000241:Adenosine; D013941:Thymine
keywords: DNA; Janus bases; base pairing; hydrogen bonding; molecular modeling