Improving The MD/QM/CSM Approach For The Characterization Of Flexible Host-guest Binding Structures

?-cyclodextrin(?-CD)and its derivatives play an important role in supramolecular chemistry.They can combine various small organic molecules into their hydrophobic cavity through hydrophobic and van der Waals interactions.They have been widely used in food,medicine,pesticide,daily chemical industry,analytical chemistry and other fields.The analysis of the binding structure of?-CD host-guest complexes is of great significance for the correct interpretation of various kinds of complexation mechanisms based on the measured binding affinities,spectra data,NMR data,and etc.Due to the complexity of the conformational space of the flexible host-guest system,it is necessary to combine certain experimental data to extract the representative conformation(RC)of the host-guest system in molecular simulation.In the study of?-CD host-guest system,based on the molecular dynamics/quantum mechanics/continuum solvent model(MD/QM/CSM)proposed by our research group,combined with induced circular dichroism(ICD)and electronic circular dichroism(ECD),representative conformations(RC)are selected,then QM/CSM is used as the free energy calculation model to calculate the host-guest binding affinity in aqueous solution.Based on the measured ICD experiment data,the computed ECD and binding affinity data of the host-guest system,we further verify the reliability of the RCs of the host-guest complexes.Based on the selected RCs,the computed host-guest interaction energy and solvent effect,we analyze the complexation mechanism of the host-guest systems at the molecular level.The influence of?-CD inclusion on the hydrolysis mechanisms of ethyl acetate and methyl p-nitrobenzoate are studied by the MD/QM/CSM approach.A variety of initial conformations were constructed for MD simulations.The RCs were screened out from the conformations along the MD trajectory.Then the hydrolysis reaction of models of ethyl acetate and methyl p-nitrobenzoate were constructed based on the RCs of their?-CD complexes obtained in the previous step.QM/CSM calculations were carried out to study the hydrolysis mechanism of methyl p-nitrobenzoate encapsulated by?-CD in aqueous solution.The computational results indicate that inclusion of?-CD hinders the hydrolysis of ethyl acetate and promotes the hydrolysis of methyl p-nitrobenzoate.In order to study the complexation mechanism of four N-methylcarbamate insecticides with?-CD,we use the improved MD/QM/CSM approach to expand the range of conformation sampling by constructing a variety of initial conformations for the studied systems.The RCs were selected based on the measured ICD data and computed ECD calculation by requiring them to be consistent.Moreover,the order of the relative stability of four host-guest systems is correctly reproduced by our QM/CSM calculation and the calculated results have a high linear correlation with the experimental values,R~2=0.99.This demonstrates that our improvement of MD/QM/CSM approach is effective and the revised approach can be applied to other flexible host-guest systems.