The Development And Application Of A MD/QM/CSM Approach To Explore Binding Mechanisms Of β-cyclodextrin And Its Derivatives

β-cyclodextrin(β-CD)and its derivatives have been widely used in environmental remediation,pharmaceutical excipients,chiral separations and food preservation,since they can encapsulate hydrophobic guest molecules to enhance their solubility and stability in aqueous solution.Generally,β-CD derivatives present stronger inclusion abilities and solubilization effect than natural β-CD.Exploring the host-guest binding mechanism is beneficial to reveal why they have different stabilities and to design high quality β-CD derivatives for various applications.We use the molecular dynamics/quantum mechanics/continuum solvent model(MD/QM/CSM)approach developed by our group in 2016 to study the binding abilities ofβ-CD and its three derivatives towards different guest molecules,i.e.naphthalenes,guanosine,artesunate.The representative conformations of β-CD and its derivatives inclusion systems are extracted from the best MD trajectories,and their binding free energies in vacuum and solvent effect are calculated to quantify the non-bonding interaction and hydrophobic interaction.Besides the semi-empirical PM3/PCM model,the DFT-D3/PCM and ONIOM2/SMD models are introduced into the QM/CSM calculations to further improve the calculation accuracy of binding affinities.All of them can correctly rank the relative stabilities of these inclusion systems in aqueous solution.In particular,the ONIOM2 method achieves satisfactory performance in calculation accuracy and calculation speed.The computational results have shown that the binding conformations and binding affinities of these inclusion systems are mainly determined by the host-guest non-bonding interaction and hydrophobic interaction.Once the guest molecule enters the CD cavity,the intermolecular hydrogen bonds between the host and guest molecules are formed to enhance the non-bonding interaction.Compared with β-CD,its three derivatives,i.e.DMCD,HPCD,SBE-β-CD,especially SBE-β-CD with negative charges,acquire more favorable hydrophobic interaction.The optimal binding mode is determined by the host-guest shape compensation.An ideal inclusion conformation can achieve a good balance between non-bonding interaction and hydrophobic interaction.In addition,the formation of the inclusion complex leads to a change in the dipole moment of the inclusion complex,which depends on the orientation of the guest molecules in the CD cavity.