These authors contributed equally to this work.
Base-Pairing Behavior of a Carbocyclic Janus-AT Nucleoside Analogue Capable of Recognizing A and T within a DNA Duplex
Version of Record online: 23 SEP 2013
Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Volume 14, Issue 16, pages 2199–2208, November 4, 2013
How to Cite
Largy, E., Liu, W., Hasan, A. and Perrin, D. M. (2013), Base-Pairing Behavior of a Carbocyclic Janus-AT Nucleoside Analogue Capable of Recognizing A and T within a DNA Duplex. ChemBioChem, 14: 2199–2208. doi: 10.1002/cbic.201300250
- Issue online: 25 OCT 2013
- Version of Record online: 23 SEP 2013
- Manuscript Received: 22 APR 2013
- base pairing;
- hydrogen bonding;
- Janus bases;
- molecular modeling
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.