The critical roles of solvent, enthalpic, and entropic contributions in complexes between different hyaluronic acid derivatives bearing monomeric β-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 noncovalent 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. 1028). 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.
The authors acknowledge the Fundação para a Ciência e a Tecnologia (FCT), Portuguese Agency for Scientific Research, through the Projects n. 016648 POCI-01-0145-FEDER-016648 and COMPETE POCI-01-0145-FEDER-007440. The Coimbra Chemistry Centre is also supported by FCT through the Projects PEst-OE/QUI/UI0313/2014 and POCI-01-0145-FEDER-007630. Tânia F. G. G. Cova and S. C. C. Nunes also acknowledge respectively the PhD and postdoctoral research Grants SFRH/BD/95459/2013 and SFRH/BPD/71683/2010, assigned by FCT. B.F.M. thanks the FCT (project CENTRO-01-0145-FEDER-000014, 2017-2020) and the Donostia International Physics Centre for financial support. The authors also thank the Laboratory for Advanced Computing (LCA) of the University of Coimbra for the provision of computer time and support.