Structural differences between the holo and the apo form in the induced fit can be difficult to address with FEP-based alchemical approaches due to the long time scale typical of these conformational transitions. Binding through conformational selection relies on the identification of the binding metastable state of the protein, sluggishly exchanging between several alternative long-lived conformations, a task that can be achieved only resorting to enhanced sampling techniques such as Hamiltonian Replica Exchange (HREM) or Metadynamics. Recently, in the context of supramolecular chemistry, two paradigmatic macrocyclic receptors have been designed for induced fit and conformational selection ligand selectivity. The first compound is a structurally flexible macrocyclic cage characterized by two distinct rapidly exchanging conformations due to the flipping of the three phenyl sidewalls connected by methylene bridges.