A general method for sequence-specific binding of peptides remains elusive despite decades of research. By creating an array of “hydrophobically coded dimples” on the surface of a surface–core doubly cross-linked micelle, we synthesized water-soluble nanoparticle receptors to recognize peptides by the location, number, and nature of their hydrophobic side chains. Minute differences in the side chains could be distinguished and affinities up to 20 nM were obtained for biologically active oligopeptides in water.

Molecular recognition of carbohydrates plays vital roles in biology but has been difficult to achieve with synthetic receptors. Through covalent imprinting of carbohydrates in boroxole-functionalized cross-linked micelles, we prepared nanoparticle receptors for a wide variety of mono- and oligosaccharides. The boroxole functional monomer bound the sugar templates through cis-1,2-diol, cis-3,4-diol, and trans-4,6-diol. The protein-sized nanoparticles showed excellent selectivity for D-aldohexoses in water with submillimolar binding affinities and completely distinguished the three biologically important hexoses (glucose, mannose, and galactose). Glycosides with nonpolar aglycon showed stronger binding due to enhanced hydrophobic interactions. Oligosaccharides were distinguished based on their monosaccharide building blocks, glycosidic linkages, chain length, as well as additional functional groups that could interact with the nanoparticles.

Molecular imprinting within cross-linked micelles using 4-vinylphenylboronate derivatives of carbohydrates provided water-soluble nanoparticle receptors selective for the carbohydrate templates. Complete differentiation of d-aldohexoses could be achieved by these receptors if a single inversion of hydroxyl occurred at C2 or C4 of the sugar or if two or more inversions took place. Glycosides with a hydrophobic aglycan displayed stronger binding due to increased hydrophobic interactions.

When disengaged interactions within a receptor are turned on by its guest, these intrahost interactions will contribute to the overall binding energy. Although such receptors are common in biology, their synthetic mimics are rare and difficult to design. By engineering conflictory requirements between intrareceptor electrostatic and hydrophobic interactions, we enabled complementary guests to eliminate the "electrostatic frustration" within the host and turn on the intrahost interactions. The result was a binding constant of Ka >10(5) M(-1) from ammonium-carboxylate salt bridges that typically function poorly in water. These cooperatively enhanced receptors displayed excellent selectivity in binding, despite a large degree of conformational flexibility in the structure.

When direct host-guest binding interactions are weakened by unfavorable solvent competition, guest-triggered intrareceptor interactions could be used to augment the binding. This strategy of cooperative enhancement, when combined with the principle of preorganization, yielded a strong and selective receptor for binding citrate in water.