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.