Theoretical Study On The Binding Ability Of Acyclic CB[4] Host To Guest Molecules

Host-guest molecules can achieve selective recognition and binding to specific guests through intermolecular non-covalent interactions,such as hydrogen bonds,hydrophobic effects,which provides new opportunities for the development of the medical materials.What's exciting is that the Cucurbit[n]uril host,CB[n],which consists of multiple glycoside units bridged by methylene groups,is used in supramolecular medical materials due to its special"pumpkin"-shaped structure and hydrophobic cavity.Regrettably,the application of CB[n]was limited by the extremely lower solubility and the skeleton rigidity.However,the acyclic cucurbit[4]uril(ACB[4])synthesized by Isaacs et al.not only reserves the excellent binding affinity of CB[n],but also improves it's solubility by introducing the soluble side-chain at the terminal aromatic groups.Based on the above advantages,ACB[4]hosts have more application opportunities in the fields of the insoluble-drug delivery and stimulus-response system.In this paper,we will concentrate on the factors that affect ACB[4]host binding ability and selective recognition to guests at the molecular level by molecular dynamics(MD)simulation and density functional theory(DFT)approaches.This will enhance the superior performance and expand the application potential of ACB[4]in novel functional materials field.The research contents of this study comprise two part:1.Clarify the factors which affect ACB[4]selectivity to guest from the molecular structure levelWith the research point of the factors affecting the selectivity ability of ACB[4]to structurally similar guests,Normorphine(NMOR),Morphine(MOR)and Morphine-3-glucuronide(M3G)were selected as the guest.The binding process of ACB[4]with guests was revealed by various MD methods.Based on the independent gradient model(IGM),the differences of host-guest interactions were visually estimated during the binding process.The host-guest binding mode and the interaction energy between ACB[4]and guests demonstrated that when the strong hydroxyl groups(-OH)of NMOR and MOR located in the hydrophobic cavity of ACB[4],the energy loss caused by the desolvation process may be not conducive to the formation of the host-guest complex;on the contrary,the glucuronide of the M3G guest located outside the apolar cavity of ACB[4]acceptors,which can not only effectively offset the effect in the desolvation process,but also provide favorable interactions with ACB[4]and water,which ensured that ACB[4]had a higher selective binding ability to M3G guest than NMOR and MOR.2.Estimate the role of H₂O to the high binding ability of ACB[4]In this work,we aimed at to reveal the role of water in the binding of the host,ACB[4],with different types of guest,such as Amiodarone(Ami),Estradiol(Est),Albendazole(Alb),Rocuronium(Roc),Indomethacin(Ind),Vecuronium(Vec).By comparing the binding behavior of host and guest molecules in aqueous solution and vacuum phase,the influence of water on the superior binding affinity of ACB[4]was studied.The MD simulation results suggested that the stronger intermolecular electrostatic interaction in the gas phase may cause the flexible structure of host and guest to be distorted,which could directly affect the stability of the inclusion complex.Unexpectedly,the presence of H₂O could weaken the unfavorable conformational transformation and strengthen the enthalpy-entropy complementarity effect to guests,meanwhile,effectively improve the binding ability of ACB[4]with different guests.