Protein-like proton exchange in a synthetic host cavity

Significance Water drives molecular interactions central to the chemistry of life. Critical to life’s metabolic machinery, enzymes catalyze reactions with remarkable selectivities and efficiencies resulting from noncovalent interactions between water, substrate, and the enzyme active site. Here, amide hydrogen–deuterium exchange kinetics provide quantification of the electronic and steric factors that influence exchange between water and a highly charged host molecule whose protective outer shell and hydrophobic cavity allow it to function like an enzyme. Investigations suggest that the host’s interior microenvironment reacts with encapsulated water in a manner that is correlated to the host’s ability to mediate acid catalysis, thereby providing a tool for developing enzyme-like microenvironments to mediate acid- or base catalysis.