Conformations and permeation mechanism into lipid bilayer of cyclodextrins

Abstract

Cyclodextrins (CDs) are potent host molecules, which can improve physical and chemical properties of guest compounds through their inclusion complexes. The binding and unbinding between guest ligand and CDs as well as the releasing into cell membrane are key factors that control the CD complex functions. Here, we aim to understand the pre-steps of that CD-ligand formation. Firstly, the conformational diversity of CD6-CD10 and CD14 was studied by the replica exchange molecular dynamics (REMD) simulations. Free CD molecules in solution were performed under the assumption that the CDs structural changes may influence the ligand binding affinity. The large ring CD (LR-CD) systems were tested for the first time with REMD simulations using various carbohydrate force fields. The structural properties and the dynamic behavior of LR-CDs corresponding to temperature changes were newly investigated. Our results indicate that: i) REMD simulation can describe the CDs conformational changes, ii) the glycam06 force field is reliable for describing the flip of glucose subunits, iii) the most probable conformations of CD10 and CD14 are bent-shape like their crystals, however, CD14 is slightly opened in comparison to the X-ray structure, iv) additionally, the various conformations of CDs could be also observed at high temperatures due to their high ring flexibility. Secondly, the pre-step of ligand transportation based on CD inclusion complexes into the membrane was studied. The micro-scale molecular dynamics (MD) simulations were used to investigated the permeation behavior of single beta-cyclodextrin (βCD) into lipid bilayer. Our results show that βCD passively diffuses into the lipid bilayer by pointing its wider rim toward the lipid polar groups and then remains at the phosphate and glycerol-ester groups with hydrogen bond formation. Moreover, the βCD derivatives (methylated- and hydroxypropyl-βCD) showed a somewhat deeper permeation that might be able to explain why these two derivatives offer a faster release of hydrophobic ligands. Our findings in this study might be helpful for the selection of proper CDs for drug transport as well as for further design of higher potent drug carriers.