Developments And Applications Of The MD/QM/CSM Approach And HGM

The host-guest system is a typical supramolecular system driven by the non-covalent interactions.It has important applications in environmental remediation,food industry,chemical analysis,chemical catalysis and biomedicine.Theoretical methods for exploring the host-guest binding mechanisms have important industrial and academic values,but their developments still face many challenges.We introduce a molecular dynamics/quantum mechanics/continuum solvation model(MD/QM/CSM)approach for investigating the host-guest binding mechanism.We use MD simulations as the conformational sampling algorithm to search for the dominant conformation of the host-guest complex,and QM/CSM model as the free energy model to calculate the host-guest binding affinity in solution.The representative conformation of the host-guest complex is validated by the high correlation between the computed and experimental binding affinity.Based on the obtained representative conformations,we analyze the non-covalent interactions and binding mode between the host and guest at the molecular level.Based on the enthalpy,entropy and solvent effect components of the binding affinity,we elucidate the host-guest binding thermodynamics.We use the MD/QM/CSM approach to investigate the binding mechanisms of the cyclodextrins with various guest molecules in aqueous solution.Among the tested QM and CSM methods,the best results were generated by the combination of PM3 and PCM/SASA methods,with a high correlation(R>0.98)between the computed and experimental affinities.For the more rigid P-CD host,the main factor that determines the stability of the inclusion complex is the matching of the shape and size of the host-guest molecules.For the more flexible DMCD host,the solvent effect manly determines the binding trends of the complexes.As an essential ingredient of MD/QM/CSM approach,the computational accuracy of solvation free energy plays an important role in the overall accuracy of MD/QM/CSM approach.We developed a semi-empirical hybrid Gaussian charge distribution model(HGM)for the generation of high-quality variable atomic radii,which were employed to construct the molecular cavity in CSM computations and ultimately produce more accurate solvation free energies.The HGM consists of atom-centered spherical Gaussian functions and discrete point charges,which partitions molecular electron density into overlapping spherical atomic domains and uses the isodensity contour concept to generate the variable atomic radii.The HGM presents a more accurate description of the electron density in the bonding region.Atomic radii of H,N and O atoms generated by the HGM exhibit larger fluctuations as the chemical environment changes.The linear correlation between the variable atomic radii of the H atom and its Mulliken charge allows us to generate the variable radii of the H atom directly from its Mulliken charge,while using the fixed Bondi radii for other heavy atoms,to construct the HGM-lH.When employed in PCM calculations,the variable atomic radii from the HGM and the HGM-lH improve the computational accuracy of the solvation free energy.