The critical roles of solvent, enthalpic, and entropic contributions in complexes between different hyaluronic acid derivatives bearing monomeric beta-cyclodextrin and adamantene moieties are assessed combining our previously designed free energy oriented method and a recently proposed density-based noncovalent interaction analysis. This establishes the relevant thermodynamics signatures and identifies the stabilizing/destabilizing non covalent interactions within the complexes used as models for the junction points. It is observed that structural variations promote major changes in the thermodynamic variables. The presence of the amphiphilic chains emphasizes inclusion and drastically increases the binding constant (to ca. 10(28)). A comprehensive thermodynamic scheme is thus provided, in which host-guest interactions, host conformation, and solvation play the leading roles. These results have direct implications for the rational design of supramolecular materials with specific properties based on these host-guest systems.