The Supramolecular "Just Right" Principle in the CB[n]S8 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 (S8) 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 S8 encapsulation, with a significant encapsulation barrier of 26.9 kcal/mol. CB[7], with an optimal PC (62%), enables stable and complete encapsulation of S8, 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.