Rationally Designed Cooperatively Enhanced Receptors To Magnify Host–Guest Binding in Water

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 <i>K</i>_a >10⁵ 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

Conformationally Switchable Water-Soluble Fluorescent Bischolate Foldamers as Membrane-Curvature Sensors

Membrane curvature is an important parameter in biological processes such as cellular movement, division, and vesicle fusion and budding. Traditionally, only proteins and protein-derived peptides have been used as sensors for membrane curvature. Three water-soluble bischolate foldamers were synthesized, all labeled with an environmentally sensitive fluorophore to report their binding with lipid membranes. The orientation and ionic nature of the fluorescent label were found to be particularly important in their performance as membrane-curvature sensors. The bischolate with an NBD group in the hydrophilic α-face of the cholate outperformed the other two analogues as a membrane-curvature sensor and responded additionally to the lipid composition including the amounts of cholesterol and anionic lipids in the membranes

Intrinsic Hydrophobicity versus Intraguest Interactions in Hydrophobically Driven Molecular Recognition in Water

Molecular recognition of water-soluble molecules is challenging but can be achieved if the receptor possesses a hydrophobic binding interface complementary to the guest. When the guest molecule contains more than one hydrophobic group, intrahost interactions between the hydrophobes could strongly influence the binding of the guest by its host. In a series of ornithine derivatives functionalized with aromatic hydrophobes, the most electron-rich compound displayed the strongest binding, despite its lowest intrinsic hydrophobicity

Sequence-Selective Binding of Oligopeptides in Water through Hydrophobic Coding

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 surface–core doubly cross-linked micelles, 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