Expanding the Topological Landscape by a G‐Column Flip of a Parallel G‐Quadruplex

Canonical G‐quadruplexes can adopt a variety of different topologies depending on the arrangement of propeller, lateral, or diagonal loops connecting the four G‐columns. A novel intramolecular G‐quadruplex structure is derived through inversion of the last G‐tract of a three‐layered parallel fold, associated with the transition of a single propeller into a lateral loop. The resulting (3+1) hybrid fold features three syn⋅anti⋅anti⋅anti G‐tetrads with a 3’‐terminal all‐syn G‐column. Although the ability of forming a duplex stem‐loop between G‐tracts seems beneficial for a propeller‐to‐lateral loop rearrangement, unmodified G‐rich sequences resist folding into the new (3+1) topology. However, refolding can be driven by the incorporation of syn‐favoring guanosine analogues into positions of the fourth G‐stretch. The presented hybrid‐type G‐quadruplex structure as determined by NMR spectroscopy may provide for an additional scaffold in quadruplex‐based technologies.