Cavity Closure Of 2-Hydroxypropyl--Cyclodextrin: Replica Exchange Molecular Dynamics Simulations

2-Hydroxypropyl--cyclodextrin (HPCD) has unique properties to enhance the stability and the solubility of low water-soluble compounds by inclusion complexation. An understanding of the structural properties of HPCD and its derivatives, based on the number of 2-hydroxypropyl (HP) substituents at the -d-glucopyranose subunits is rather important. In this work, replica exchange molecular dynamics simulations were performed to investigate the conformational changes of single- and double-sided HP-substitution, called 6-HPCDs and 2,6-HPCDs, respectively. The results show that the glucose subunits in both 6-HPCDs and 2,6-HPCDs have a lower chance of flipping than in CD. Also, HP groups occasionally block the hydrophobic cavity of HPCDs, thus hindering drug inclusion. We found that HPCDs with a high number of HP-substitutions are more likely to be blocked, while HPCDs with double-sided HP-substitutions have an even higher probability of being blocked. Overall, 6-HPCDs with three and four HP-substitutions are highlighted as the most suitable structures for guest encapsulation, based on our conformational analyses, such as structural distortion, the radius of gyration, circularity, and cavity self-closure of the HPCDs.