A Theoretical Study On The Complexation Mechanism Of Cyclodextrin And Cucurbit Uril[7] Host-Guest Systems Using MD/QM/CSM Approach

The host-guest system is a typical supramolecular system driven by the non-covalent interactions.It has play an important role in many areas.Due to the unique structural characteristics of ?-CD,molecular ‘the hydrophobic outer and hydrophilic inner' and it can provide a hydrophobic binding site like an enzyme.The host molecule can envelops various guest molecules,such as organic molecules,inorganic molecules,and various suitable molecules.Cucurbit uril is another main molecule as cyclodextrin.It is a barrel-like cyclic compound.It has the same opening at both ends and the cavity is surrounded by carbonyl.It is made in the middle and can contain organic molecules.Theoretical studies have been extensively carried out to explore the host-guest binding mechanisms and provided valuable insights for experimental investigations,however the currently available theoretical approaches are still facing many challenges.In this paper,we use the molecular dynamics/quantum mechanics/continuous solvent model method(MD/QM/CSM method)developed in our group to study the binding mechanisms of ?-cyclodextrins(?-CD)and cucurbit uril(CB[7])with different guest molecules in aqueous solution..We use MD simulations and cluster analysis to predict the representative binding conformations of host-guest complex systems.Then,the QM/CSM model is employed to compute the host-guest binding affinity in aqueous solution.Semi-empirical PM3 method is used to calculate the binding free energy in vacuum,while the solvent effect is calculated using the polarizable continuum model(PCM)and density functional theory(DFT).MD/QM/CSM method calculated host-guest systems composite free energy has a high linear correlation with the experimental values,and the thermodynamic stability ranking of different host-guest systems is accurately given.This shows the rationality and reliability of the theoretical model and calculation results.Based on the reprensntative conformation was extracted by the MD simulations and from microscopic(structure)to reveal the mode of host-guest combination.And then QM/CSM as the calculation mode to calculate enthalpy,entropy and the solvent effect components of the binding affinity,we illustrate the host-guest binding thermodynamics.In this paper,we will study the following aspects.(1)Cyclodextrin has the ability of recognizing chirality and can recognize chiral drug molecules.Therefore,cyclodextrin is used as a chiral selector.The four chiral drug molecules have the same aromatic ring and chiral center was selected in this paper.In this dissertation,the relative inclusion capacity of cyclodextrin to these four chiral drug molecules was studied by using MD/QM/CSM method,and the recognition mechanism of cyclodextrin to chiral molecules was revealed.The compound free energy calculated in this paper is consistent with the experiment.The analysis of the compound free energy reveals the reason for the resolution of the cyclodextrin to chiral drug molecule.The vacuum inclusion free energy and the solvent effect are jointly determined.Moreover,the difference in the resolution of cyclodextrin chiral molecules may also be related to the relative size of the molecules.The larger the molecule,the better the resolution effect.(2)In this paper,the MD/QM/CSM method developed by our research group is used to study the relative inclusion capacity of natural cyclodextrin and2-methyl-?-cyclodextrin with three naphthol molecules.The representative composite conformation extracted by MD simulation was used to calculate the free energy of the host and guest.The results were consistent with the experiments.The inclusion ability of cyclodextrin to naphthol molecules can be sorted normally.The inclusion ability of2-methyl-?-cyclodextrin on naphthol molecules is better than that of natural cyclodextrin.It may be that methylation of natural cyclodextrin hydroxyl groups has enhanced the inclusion ability of naphthol molecules by cyclodextrin..(3)In this paper,the MD/QM/CSM method developed by our research group is used to study the relative inclusion capacity of cucurbituril with three perfluoride compounds.The calculation results are inconsistent with the experimental results.It is possible that the PM3/PCM method used in the calculation of the cucurbituril system cannot accurately rank its relative inclusion capacity.For the calculation of the cucurbiturol system,different calculation methods need to be developed.