Molecular dynamics simulations and MM-PBSA calculations of the cyclodextrin inclusion complexes with 1-alkanols, para-substituted phenols and substituted imidazoles

Molecular dynamics (MD) simulations using the Amber force field have been applied to obtain detailed information on inclusion complex formation between natural cyclodextrins (CDs) and organic molecules (1-alkanols, substituted phenols, and substituted imidazoles). The obtained MD trajectories were used to estimate the binding free energy of each guest/CD complex using the molecular mechanics/Poisson Boltzmann surface area (MM-PBSA) method. The calculated relative binding free energies of the inclusion complexes of some organic compounds with α- and β-CDs were in good agreement with the experimental data though the absolute values were not. Inspection of the binding free energy components revealed the dominant contribution of van der Waals interactions to inclusion complex stability. Both guest-host electrostatic interactions and the hydrophobic effect do also contribute to complex stability. It was also apparent from the calculations that the flexibility of the guest molecule has a significant contribution to complex stability.