The Supramolecular “Just Right” Principle in the CB[ n ]S 8 Goldilocks Triad: Dynamic and Interaction Energy Considerations in the CB[ n ]S8 ( n = 6, 7, 8) Formation from MD+EDA Calculations

The formation of host–guest species is a relevant issue in obtaining biologically desired active structures, supramolecular arrays, among other species. In this work, the encapsulation behavior of elemental sulfur (S 8 ) within different cucurbituril hosts CB[6], CB[7], and CB[8] emphasizes the critical role of size compatibility and packing coefficient (PC) in host–guest interactions. CB[6] exhibits a high packing coefficient (PC) of 103% and prevents S 8 encapsulation, with a significant encapsulation barrier of 26.9 kcal/mol. CB[7], with an optimal PC (62%), enables stable and complete encapsulation of S 8, stabilized primarily through electrostatic and London dispersion forces, overcoming a moderate barrier of 17.1 kcal/mol. In contrast, CB[8] presents a loose fit (PC of 41%), facilitating dynamic encapsulation and release due to a low barrier of 5.7 kcal/mol, with London dispersion as the dominant stabilizing force. The combined molecular dynamics and energy decomposition analysis (MD+EDA) approach elucidates the dynamic stages of host–guest interaction denoted by an initial contact, incorporation, and inclusion, revealing the interplay of steric hindrance, electrostatics, and dispersion forces. These findings deepen the understanding of molecular recognition and self-assembly in cucurbituril systems, providing a framework for designing host molecules with tailored binding properties for supramolecular chemistry and related applications.