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00925njm 22002777a 4500 dc Assi, Hala Abou author Harkness, Robert W author Martin-Pintado, Nerea author Wilds, Christopher J author Campos Olivas, Ramon author Mittermaier, Anthony K author Gonzalez, Carlos author Damha, Masad J author 2016-06-20 i-Motifs are four-stranded DNA structures consisting of two parallel DNA duplexes held together by hemi-protonated and intercalated cytosine base pairs (C:CH(+)). They have attracted considerable research interest for their potential role in gene regulation and their use as pH responsive switches and building blocks in macromolecular assemblies. At neutral and basic pH values, the cytosine bases deprotonate and the structure unfolds into single strands. To avoid this limitation and expand the range of environmental conditions supporting i-motif folding, we replaced the sugar in DNA by 2-deoxy-2-fluoroarabinose. We demonstrate that such a modification significantly stabilizes i-motif formation over a wide pH range, including pH 7. Nuclear magnetic resonance experiments reveal that 2-deoxy-2-fluoroarabinose adopts a C2'-endo conformation, instead of the C3'-endo conformation usually found in unmodified i-motifs. Nevertheless, this substitution does not alter the overall i-motif structure. This conformational change, together with the changes in charge distribution in the sugar caused by the electronegative fluorine atoms, leads to a number of favorable sequential and inter-strand electrostatic interactions. The availability of folded i-motifs at neutral pH will aid investigations into the biological function of i-motifs in vitro, and will expand i-motif applications in nanotechnology. Nucleic Acids Res. 2016;44(11):4998-5009. 10.1093/nar/gkw402 1362-4962 0305-1048 Nucleic acids research 27166371 http://hdl.handle.net/20.500.12105/7884 Stabilization of i-motif structures by 2'-β-fluorination of DNA