Unraveling Biomimetic Hydrogen Bonds of Dinucleotides by a Crown‐Ether‐Functionalized Tetraphenylethene‐Based Cage

Abstract Natural biological systems achieve precise recognition and regulation of nucleic acids through multi‐domain synergistic interactions. Herein, we report the design and synthesis of a crown‐ether‐functionalized tetraphenylethene‐based cage ( 1 •8X, X = PF 6 ˉ or Clˉ) with two distinct recognition sites—four flexible, amphiphilic 18‐crown‐6 (18‐C‐6) units and a rigid, hydrophobic cavity. Its multi‐cavity architecture offers an enzyme‐like microenvironment, replicating the cooperative recognition behavior seen in natural receptors. As a result, 1 •8Clˉ promotes distinctive hydrogen‐bonded assemblies of dinucleotides with various sequences in aqueous environments. Notably, 1 •8Clˉ facilitates a stable G•C•G•C quartet upon binding with two d(GpC), while assembling into an unprecedented C•C•C•C quartet in a 1:4 stoichiometric ratio with d(CpC). Additionally, 1 •8Clˉ selectively recognizes the 5′‐base of dinucleotides or specifically binds to T base, promoting the formation of non‐classical base‐pairing patterns such as G•G, T•(H 2 O) 2 •T, and T•(K + )•T dimers in crystalline states. This study systematically investigates the hydrogen‐bonding patterns of dinucleotides in biomimetic environments, providing new insights into the design of biomimetic receptors and understanding the diversity of non‐classical nucleic acid structures.