Additionally, in order to study the effect of the CDs on the CUR conformational change that can be adapted into the cavity, as well as their influence on the binding property, the CUR/CD complexes were subjected to the MC simulations implemented in the ROSETTA code (Meiler et al., 2006), and 50 ns MD simulations with the MM-GBSA approach in evaluating binding affinity. To approximate the MD simulations in a more or less realistic way, all the primary hydroxyl groups were substituted with hydroxypropyl residues, in the case of cyclodextrin models. Together with the trajectory analysis of the CUR into the CDs (Supplementary material 1-4), the energetic analysis was performed throughout the MC and MD simulations. The calculations show that the highest CD binding affinity to CUR belongs to HP-γ-CD, after ligand hydration with the ΔGMM-GBSA value of −86.38 kcal*mol-1 and ΔGbind value of −94.25 kcal*mol-1, as a result of strong hydrophobic (vdW) forces leading an, and a decrease in the CUR hydration, followed by excessive desolvation effects as increase in water displacement (Figure 5 and 6). On the other hand, the hydration/desolvation effect for CUR/γ-CD characterized by less water displacement and high ligand hydration was more pronounced, but the hydrophobic (vdW) forces were less prominent.