Noncovalent Interactions within a Synthetic Receptor Can Reinforce Guest Binding

Structural and thermodynamic data are presented on the binding properties of anion receptors
containing two covalently linked cyclopeptide subunits that bind sulfate and iodide anions with micromolar
affinity in aqueous solution. A synchrotron X-ray crystal structure of the sulfate complex of one receptor
revealed that the anion is bound between the peptide rings of the biscyclopeptide. Intimate intramolecular
contacts between the nonpolar surfaces of the proline rings of the individual receptor moieties in the complex
suggest that hydrophobic interactions within the receptor that do not directly involve the guest contribute
to complex stability. This finding is supported by a microcalorimetric analysis of the solvent dependence of
complex stability, which showed that increasing the water content of the solvent has only a weak influence
on the Gibbs energy of binding. Hence, the increasing amount of energy required for desolvating the binding
partners in solutions containing more water is almost compensated by the increasingly favorable hydrophobic
interactions. Further observations that suggest that guest-induced intra-receptor interactions contribute to
guest binding are (i) anion binding of a monomeric cyclopeptide lacking the covalent linkage between the
two rings leads to the formation of 2:1 complexes; (ii) in the crystal structure of the 2:1 iodide complex of
this monotopic receptor, a similar arrangement of the two cyclopeptide rings has been found as in the
sulfate complex of the biscyclopeptide; (iii) complex formation of the monomeric cyclopeptide in aqueous
solution is highly cooperative with a large stability constant corresponding to the formation of the 2:1
complexes from relatively instable 1:1 complexes; (iv) the monomeric cyclopeptide forms only 1:1 anion
complexes in DMSO where hydrophobic interactions do not take place; and (v) introducing polar hydroxy
groups on the proline rings of the monomeric cyclopeptide disrupts cooperativity causing the formation of
only 1:1 complexes even in aqueous solution. Taken together these observations demonstrate that, in
addition to direct receptor−substrate interactions, noncovalent interactions between the two subunits of
such biscyclopeptides contribute significantly to anion complex stability. Reinforcement of molecular
recognition through intra-receptor interactions should be an attractive new strategy to boost host−guest
affinities.