Spatial Matching Selectivity and Solution Structure of Organic–Metal Hybrid to Quadruplex–Duplex Hybrid

Abstract The sequence‐dependent DNA secondary structures possess structure polymorphism. To date, studies on regulated ligands mainly focus on individual DNA secondary topologies, while lack focus on quadruplex–duplex hybrids (QDHs). Here, we design an organic–metal hybrid ligand L 1 Pt(dien) , which matches and selectively binds one type of QDHs with lateral duplex stem‐loop (QLDH) with high affinity, while shows poor affinity for other QDHs and individual G4 or duplex DNA. The solution structure of QLDH MYT1L‐ L 1 Pt(dien) complex was determined by NMR. The structure reveals that L 1 Pt(dien) presents a chair‐type conformation, whose large aromatic “chair surface” intercalates into the G‐quadruplex‐duplex interface via π–π stacking and “backrest” platinum unit interacts with duplex region through hydrogen bonding and electrostatic interactions, showing a highly matched lock‐key binding mode. Our work provided guidance for spatial matching design of selectively targeting ligands to QDH structures.