*3.1. Model Preparation*

The 3D structure of 3HF (Figure 1A) was generated by GaussView version 6.0 [55]. To investigate the effect of water on PT process, a water molecule near the PT site of 3HF was placed between the H1 and O2 atoms to model 3HF with a water molecule (3HFW). The 3HF and 3HFW structures were fully optimized with DFT and TD-DFT methods using Gaussian 16, Revision C.01 [56]. The γ-CD structure extracted from the co-crystal structure of cyclo/maltodextrin-binding protein in complex with γ-CD (PDB code: 2ZYK) was used in this study. To obtain the inclusion complex, encapsulation of the optimized 3HF into γ-CD's cavity was performed by molecular docking with 100 runs using the CDOCKER module in the Accelrys Discovery Studio 2.5 (Accelrys Software Inc., San Diego, CA, USA). The three docked inclusion complexes with the lowest CDOCKER interaction energy for the chromone ring (C-ring, Form I) and phenyl ring (P-ring, Form II) insertion into the hydrophobic cavity of the γ-CD were selected for MD simulations (MD1-MD3 for Form I and Form II). The most stable 3HF/γ-CD inclusion complexes in Form I and Form II from a docking study were fully optimized at PBE0/def2-SVP level of theory for investigating PT reaction. Note that, these Form I and Form II were used as the additional initial structures for MD simulations, MD4. To study the effect of water associated in PT for 3HF encapsulated in γ-CD, a water molecule was added to form interHBs with 3HF both in Form I and Form II namely Form I-W and Form II-W, respectively. Then, Form I-W and Form II-W were fully optimized with DFT and TD-DFT methods.
