Elucidating the mechanism of substrate encapsulation in supramolecular resorcin[4]arene using enhanced sampling simulations

Supramolecular cages have emerged as promising catalysts for diverse chemical transformations. Analogous to enzymes, these cage catalysts utilize non-covalent interactions to encapsulate substrates within their well-defined cavities, thereby enabling highly selective catalysis. Among them, resorcin[4]arene-based supramolecular cages have gained particular interest due to their structural versatility and catalytic potential. While significant progress has been made in understanding chemical reactions occurring within these confined environments, the detailed mechanisms governing the substrate binding and release to and from the cage cavity remain poorly understood. In this study, we employ on-the-fly probability-based enhanced sampling simulations to delineate the mechanism of reversible encapsulation and de-capsulation of a substrate in the supramolecular resorcin[4]arene cage. Our findings reveal that substrate encapsulation-decapsulation preferentially occurs through water-accessible regions of the cage, facilitated by the transient disruption of hydrogen bonds between its constituent units. The calculated free energy landscape indicated an energy barrier of 5.0 ± 1.0 kcal mol^-1 for the decapsulation and 1.5 ± 1.0 kcal mol^-1 for encapsulation processes, suggesting facile substrate exchange between the cage and the solution. The atomistic and dynamic insights into the substrate uptake/release mechanisms will have implications for the rational design of tunable supramolecular catalysts.