Formation of left-handed helices by C2′-fluorinated nucleic acids under physiological salt conditions

Author:

El-Khoury Roberto1,Cabrero Cristina2,Movilla Santiago3,Kaur Harneesh1,Friedland David1,Domínguez Arnau14,Thorpe James D1,Roman Morgane1,Orozco Modesto3,González Carlos2ORCID,Damha Masad J1ORCID

Affiliation:

1. Department of Chemistry, McGill University , Montreal , Quebec H3A 0B8, Canada

2. Instituto de Química Física Blas Cabrera , CSIC, Serrano 119, 28006 Madrid, Spain

3. Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST) , 08028 Barcelona, Spain

4. IQAC-CSIC , Jordi Girona 18-26, 08034 Barcelona, Spain

Abstract

Abstract Recent findings in cell biology have rekindled interest in Z-DNA, the left-handed helical form of DNA. We report here that two minimally modified nucleosides, 2′F-araC and 2′F-riboG, induce the formation of the Z-form under low ionic strength. We show that oligomers entirely made of these two nucleosides exclusively produce left-handed duplexes that bind to the Zα domain of ADAR1. The effect of the two nucleotides is so dramatic that Z-form duplexes are the only species observed in 10 mM sodium phosphate buffer and neutral pH, and no B-form is observed at any temperature. Hence, in contrast to other studies reporting formation of Z/B-form equilibria by a preference for purine glycosidic angles in syn, our NMR and computational work revealed that sequential 2′F…H2N and intramolecular 3′H…N3′ interactions stabilize the left-handed helix. The equilibrium between B- and Z- forms is slow in the 19F NMR time scale (≥ms), and each conformation exhibited unprecedented chemical shift differences in the 19F signals. This observation led to a reliable estimation of the relative population of B and Z species and enabled us to monitor B–Z transitions under different conditions. The unique features of 2′F-modified DNA should thus be a valuable addition to existing techniques for specific detection of new Z-binding proteins and ligands.

Funder

National Science and Engineering Council of Canada

Spanish ‘Ministerio de Ciencia e Innovación’

Center of Excellence for HPC H2020 European Commision

Centre of Excellence for Computational Biomolecular Research

Instituto de Salud Carlos III–Instituto Nacional de bioinformática

Fondo Europeo de Desarrollo Regional

ERFD Operative Programme for Catalunya, the Catalan Government AGAUR

Publisher

Oxford University Press (OUP)

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