Free-Energy Calculations For Study On Properties Of Cyclodextrins And Association Mechanism With Drugs

Cyclodextrins(CDs) have a hydrophilic outer surface and a hydrophobic inner core,conducive for the formation of inclusion complexes through the binding of the small molecules into their cavity.This property has attracted increasing attention in food field,pharmaceutical science,etc.Although experimental methods have been employed to investigate the inclusion process,the association mechanism is until now somewhat fragmentary.Theoretical approaches offer the three-dimension structure, the stability of the complex structure and binding free energy information.In this dissertation,molecular simulations were used toinvestigate the properties of CDs and the complexes of CDs with different guests.(1) The molecular dynamics(MD) simulations describing the hydration process forα-,β-andγ-CDs have been performed.The results reported here demonstrate that the anomalous solubility forβ-CD can be essentially rationalized by its greater rigidity conferred by the participating intramolecular hydrogen bonds and the higher density of water molecules of lesser mobility.The hydration free energy ofα-,β-andγ-CD was computed using the free energy perturbation(FEP) method.This quantity is shown to increase with the number of glucose units,thereby suggesting that the anomalous solubility ofβ-CD cannot be explained by its free energy of hydration alone.(2) The structures and interactions ofα-,β-,andγ-CD dimers and 6-O-(4-hydroxybenzoyl)-β-CD(HB-β-CD) dimers were simulated by MD methods in vacuum and in an aqueous solution,respectively.The binding free energies of three possible arrangements(head-to-head,head-to-tail,and tail-to-tail) of each dimer were calculated using the FEP method.The results show that the stable arrangements forα-,β-,andγ-CD dimers in vacuum are head-to-head motifs due to the contribution of the intermolecular hydrogen bonds.In the aqueous solution,the solvent exerts more influence on the structures of the natural CD dimers than on the HB-β-CD dimer, resulting in a decrease of the stability of the formers.From the calculated binding free energies,the HB-β-CD dimer in the aqueous solution is much more stable than theβ-CD dimer. (3) Free-energy calculations characterizing the inclusion of three steroidal drugs, viz.hydrocortisone(Hyc),progesterone(Pro) and Testosterone(Tes),intoβ-CD, following two possible relative orientations,have been carried out,employing adaptive biasing force(ABF) and FEP methods.In the light of the analysis of the free-energy profiles determined using the ABF method along the chosen model reaction coordinate,orientationⅠis suggested to be favored for Hyc and Tes,albeit orientationⅡappears to be favored for Pro.Moreover,van der Waals interactions are shown to constitute the main driving forces responsible for the inclusion process in the preferred orientation.Additional MD simulations of the complexes at the global minimum of the free-energy surface were also performed.Analysis of the trajectories suggests that in contrast with Hyc-β-CD and Tes-β-CD,transition between the most thermodynamically stable structure of Pro-β-CD and the second stable structure can be witnessed.(4) The inclusion complexes and interactions ofβ-CD and imipramine(IMI) with stoichiometries of 1:2,1:1,and 2:1 were simulated by MD methods in the gas phase and in an aqueous solution,respectively.The binding free energies of four possible complexes were calculated using the FEP method based on pre-designed thermodynamic cycles,suggesting that the 2:1 inclusion mode is the most energetically favorable,both in the gas and aqueous phases.The van der Waals interactions and intermolecular hydrogen-bond interactions between twoβ-CDs constitute the main contribution to the stability of the complex.In addition,at variance with in the gas phase,among three possible 1:1β-CD-IMI structures,two orientations of IMI with benzene ring located inside the cavity ofβ-CD are more favorable than that with the side chain inside the cavity in the aqueous solution.The van der Waals interactions are shown to play a major role in stabilizing the 1:1 complex structure in the two phases.