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

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 L1Pt(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‐L1Pt(dien) complex was determined by NMR. The structure reveals that L1Pt(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. The solution structure of quadruplex‐lateral duplex hybrid (QLDH) MYT1L‐L1Pt(dien) complex shows that L1Pt(dien) presents a chair‐type conformation, whose large aromatic “chair surface” intercalates into the G4‐duplex interface via π–π stacking, and “backrest” platinum unit interacts with duplex region through hydrogen bonding and electrostatic interactions, displaying a highly matched lock‐key binding mode.