Abstract β-Cyclodextrin (β-CD) is a widely used host molecule in supramolecular chemistry, pharmaceutical formulations, and chiral recognition. However, its conformational flexibility, critical to the thermodynamics and geometry of its inclusion complexes, is often underrepresented in computational modeling. In this study, we present a large-scale conformational analysis of β-CD to support accurate modeling of its inclusion complexes. A total of 437 β-CD conformations were extracted from 293 Cambridge Structural Database entries and optimized using B3LYP-D3/6-31G(d,p) both in vacuo and with an implicit water PCM model. Hierarchical clustering of Gibbs free energies revealed 18 major conformational clusters (in vacuo) and 17 (PCM) spanning approximately 40 kcal/mol. Simulated annealing and quench dynamics from the most and least stable geometries yielded low-energy conformers, four of which converged to a new global minimum approximately 9 kcal/mol below any experimental structure. A moderate correlation (Spearman r ≈ 0.60) between vacuum and solvated Gibbs free energy values indicates solvent-dependent reordering. Guest molecule descriptors were also analyzed to explore host-guest structural correlations. Cartesian coordinates for 19 representative β-CD conformers are provided as a ready-to-use resource for molecular modeling, ensemble docking and free energy studies. These findings highlight the importance of conformational selection in accurately modeling β-CD inclusion complexes and may enhance binding affinity predictions, with direct application in drug delivery and chiral recognition.
Napiórkowska et al. (Mon,) studied this question.