Inclusion of Levodopa into β-Cyclodextrin: A Comprehensive Computational Study

[Image: see text] This study focused on the inclusion of levodopa (LVDP) into β-cyclodextrin (BCD) using various computational methods such as quantum mechanics (QM), molecular dynamics/steered molecular dynamics (MD/SMD), and QM/molecular mechanics/Poison–Boltzmann surface area (QM/MM/PBSA). The QM results assigned the most significant charge-transfer atoms and the higher stability of LVDP in the aqueous phase. The MD results indicate the formation of a 1:1 complex with a reasonable estimation of the effective radius of the complex, the significant contribution of hydrogen bonding in the binding energy, and the enhancement of the water solubility of LVDP. By accounting for the water hydrogen bonds and their dipolar effects, QM/MM calculations lead to the more accurate IR spectrum and binding energy of the BCD–LVDP complex. By considering carboxylic and amine functional groups’ more precise arrangement, QM/MM assigns stronger hydrogen bonds between LVDP and BCD. While all the methods provide a reasonable estimation of the binding energy, the most accurate value (−4.14 kcal/mol) is obtained from QM/MM/PBSA.