Flipping a G‐Tetrad in a Unimolecular Quadruplex Without Affecting Its Global Fold

A unimolecular G‐quadruplex with a hybrid‐type topology and propeller, diagonal, and lateral loops was examined for its ability to undergo structural changes upon specific modifications. Substituting 2′‐deoxy‐2′‐fluoro analogues with a propensity to adopt an anti glycosidic conformation for two or three guanine deoxyribonucleosides in syn positions of the 5′‐terminal G‐tetrad significantly alters the CD spectral signature of the quadruplex. An NMR analysis reveals a polarity switch of the whole tetrad with glycosidic conformational changes detected for all four guanine nucleosides in the modified sequence. As no additional rearrangement of the overall fold occurs, a novel type of G‐quadruplex is formed with guanosines in the four columnar G‐tracts lined up in either an all‐syn or an all‐anti glycosidic conformation.