Structural Differences at Quadruplex-Duplex Interfaces Enable Ligand-Induced Topological Transitions

Quadruplex-duplex (QD) junctions, which represent unique structural motifs of both biological and technological significance, have been shown to constitute high-affinity binding sites for various ligands. A QD hybrid construct based on a human telomeric sequence, which harbors a duplex stem-loop in place of a short lateral loop, is structurally characterized by NMR. It folds into two major species with a (3+1) hybrid and a chair-type (2+2) antiparallel quadruplex domain coexisting in a K⁺ buffer solution. The antiparallel species is stabilized by an unusual capping structure involving a thymine and protonated adenine base AH⁺ of the lateral loop facing the hairpin duplex to form a T·AH⁺·G·C quartet with the interfacial G·C base pair at neutral pH. Addition and binding of Phen-DC₃ to the QD hybrid mixture by its partial intercalation at corresponding QD junctions leads to a topological transition with exclusive formation of the (3+1) hybrid fold. In agreement with the available experimental data, such an unprecedented discrimination of QD junctions by a ligand can be rationalized following an induced fit mechanism.