Host–guest complexation of progesterone with β-cyclodextrin derivatives: hydration structure, binding thermodynamics, and loading pathways from molecular dynamics simulations

Progesterone (PROG) is a poorly water-soluble steroid whose formulation remains challenging despite the broad pharmaceutical utility of cyclodextrins (CDs). Here, atomistic molecular dynamics simulations combined with umbrella sampling and potential of mean force (PMF) reconstruction were used to compare the inclusion behavior of PROG in native beta-cyclodextrin (betaCD) and three pharmaceutically relevant R2-substituted derivatives, namely 2-methyl-betaCD, 2-hydroxypropyl-betaCD, and 2-sulfobutylether-betaCD. Twenty independent host-guest systems were constructed to characterize loading pathways, structural adaptation of the host cavity, hydration reorganization, and thermodynamic preference. The results show that R2 functionalization strongly modulates both directional selectivity of guest entry and the free-energy landscape of encapsulation. PROG binding induces a systematic reorganization of the cyclodextrin scaffold toward thicker, more circular, and more symmetric toroidal conformations, while partially dehydrating the cavity and perturbing the local tetrahedral structure of confined water. PMF analysis revealed pathway-dependent differences in the depths and shapes of the free-energy wells along the selected dissociation coordinate. Among the investigated pathways, particularly deep PMF minima were observed for specific loading pathways of 2-hydroxypropyl-betaCD and 2-sulfobutylether-betaCD. Across all carriers, van der Waals interactions dominate the direct short-range PROG-CD interaction, whereas short-range interactions between the PROG-CD complexes and surrounding water are strongly dependent on substituent chemistry. In particular, 2-sulfobutylether-betaCD exhibits markedly more negative short-range complex-water interaction energies, primarily because of the electrostatic interactions between its sulfonate groups and surrounding water. These findings provide molecular-level insight into how cyclodextrin functionalization governs progesterone encapsulation and may guide the rational design of CD-based delivery systems.