Dramatic Effect of Furanose C2′ Substitution on Structure and Stability: Directing the Folding of the Human Telomeric Quadruplex with a Single Fluorine Atom

Human telomeric DNA quadruplexes can adopt different conformations in solution. We have found that arabinose, 2′F-arabinose, and ribose substitutions stabilize the propeller parallel G-quadruplex form over competing conformers, allowing NMR structural determination of this particularly significant nucleic acid structure. 2′F-arabinose substitution provides the greatest stabilization as a result of electrostatic (F–CH---O4′) and pseudo-hydrogen-bond (F---H8) stabilizing interactions. In contrast, 2′F-rG substitution provokes a dramatic destabilization of the quadruplex structure due to unfavorable electrostatic repulsion between the phosphate and the 2′-F.