Fluorine‐Mediated Editing of a G‐Quadruplex Folding Pathway

A (3+1)‐hybrid‐type G‐quadruplex was substituted within its central tetrad by a single 2′‐fluoro‐modified guanosine. Driven by the anti ‐favoring nucleoside analogue, a novel quadruplex fold with inversion of a single G‐tract and conversion of a propeller loop into a lateral loop emerges. In addition, scalar couplings across hydrogen bonds demonstrate the formation of intra‐ and inter‐residual F ⋅⋅⋅ H8−C8 pseudo‐hydrogen bonds within the modified quadruplexes. Alternative folding can be rationalized by the impact of fluorine on intermediate species on the basis of a kinetic partitioning mechanism. Apparently, chemical or other environmental perturbations are able to redirect folding of a quadruplex, possibly modulating its regulatory role in physiological processes.