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Beta cyclodextrin (βCD) is well-known as a potent drug carrier improving drug solubility, stability, and bioavailability. The water layer adjacent to the membrane surface and lipophilic domain itself are a controlling barrier for drug transport. However, the molecular details of the interaction between βCD and the lipid membrane has not yet been clearly explained. Here, molecular dynamics simulations were performed to visualize the interaction process of the βCD molecule with the lipid bilayer for six microseconds in total. Our results show that βCD passively diffuses into the lipid bilayer by pointing its open secondary rim toward the lipid polar groups and then remains at the phosphate and glycerol-ester groups with hydrogen bond formation. The information obtained from this study may suggest that the association of βCD at the cellular membrane plays an important role for the transfer of drug and the extraction of cholesterol.

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Understanding the atomic level interactions and the resulting structural characteristics is required for developing beta-cyclodextrin (βCD) derivatives for pharmaceutical and other applications. The effect of four different solvents on the structures of the native βCD and its hydrophilic (methylated βCD; MEβCD and hydroxypropyl βCD; HPβCD) and hydrophobic derivatives (ethylated βCD; ETβCD) were explored using molecular dynamics (MD) simulations and solvation free energy calculations. The native βCD, 2-MEβCD, 6-MEβCD, 2,6-DMβCD, 2,3,6-TMβCD, 6-HPβCD, 2,6-HPβCD and 2,6-ETβCD in non-polar solvents (cyclohexane; CHX and octane; OCT) were stably formed in symmetric cyclic cavity shape through their intramolecular hydrogen bonds. In contrast, βCDs in polar solvents (methanol; MeOH and water; WAT) exhibited large structural changes and fluctuations leading to significant deformations of their cavities. Hydrogen bonding with polar solvents was found to be one of the major contributors to this behavior: solvent-βCD hydrogen bonding strongly competes with intramolecular bonding leading to significant changes in structural stability of βCDs. The exception to this is the hydrophobic 2,6-ETβCD which retained its spherical cavity in all solvents. Based on this, it is proposed that 2,6-ETβCD can act as a sustained release drug carrier.