Coarse-grained representation of cucurbiturils in aqueous media within the Martini 3 force field

Cucurbit[n]urils (CB[n]s) are a class of synthetic cavitands well-suited for host-guest complexation owing to their capacity to accommodate a broad range of neutral and cationic species with diverse structural features. Elucidating the geometry and dynamics of the resulting complexes, together with their supramolecular assemblies with potential applications in nanotechnology and materials science, is an active area of contemporary research. In the present study, we employed molecular dynamics (MD) simulations to construct coarse-grained models for CB[n] (n = 6-8), designed to be compatible with the Martini 3 force field. Parameter optimization was performed following the standard procedure of matching structural characteristics and the free energies of transfer between octanol and water as obtained from atomistic MD simulations. Our results show that the models generated using this approach accurately reproduce the size and shape of the cavitands, as well as the hydration patterns of their cavities. The validity of the models was demonstrated through the reproduction of interactions with encapsulated amino acids, namely, Met and Leu in CB[6], and Tyr and Trp in CB[7]. The models additionally predicted the stability and configurational behavior of the corresponding host-guest complexes. The accuracy of the models was further assessed by analyzing the relative orientation and mobility of three nitroxide spin probes [TEMPO (2,2,6,6-tetramethylpiperidinyl-1-oxy), 4-carboxy-TEMPO, and 4-amino-TEMPO] inside CB[7] and CB[8] cavities. Reasonable agreement was achieved for spin probe encapsulation in CB[7] upon refinement of the bead type assigned to the nitroxide fragment, whereas the mobility within the CB[8] cavity was overestimated, particularly in the case of the 4-amino-TEMPO probe.