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Host–guest interactions have been increasingly explored for use in the dynamic physical crosslinking of polymeric precursors to form hydrogel networks. However, the orientation of guest motifs is restricted upon macromolecule conjugation. The implications of such restriction on both the kinetics and thermodynamics of the resulting host–guest supramolecular crosslinks are poorly understood. Herein, guest crosslinking motifs from controlled regioisomers are demonstrated to yield distinct material properties. Moreover, the underlying phenomena point to further unexpected impact of modular guest topology manifest on the molecular scale in both the affinity and dynamics of supramolecular complex formation. 

Host–guest interactions are important to the design of pharmaceuticals and, more broadly, to soft materials as they can enable targeted, strong, and specific interactions between molecules. The binding process between the host and guest may be classified as a “rare event” when viewing the system at atomic scales, such as those explored in molecular dynamics simulations. To obtain equilibrium binding conformations and dissociation constants from these simulations, it is essential to resolve these rare events. Advanced sampling methods such as the adaptive biasing force (ABF) promote the occurrence of less probable configurations in a system, therefore facilitating the sampling of essential collective variables that characterize the host–guest interactions. Here, we present the application of ABF to a rod–cavitand coarse-grained model of host–guest systems to acquire the potential of mean force. We show that the employment of ABF enables the computation of the configurational and thermodynamic properties of bound and unbound states, including the free energy landscape. Moreover, we identify important dynamic bottlenecks that limit sampling and discuss how these may be addressed in more general systems.