Molecular modeling methodology of beta-cyclodextrin inclusion complexes

A docking approach for molecular mechanics optimization of beta-cyclodextrin complexes is described. Because of the specific geometry of the cyclodextrins and the class of guests (relatives of tert-butyl benzene), the guest molecule is moved along a vector going through the middle of the cavity. This vector is perpendicular to the mean plane of the acetal oxygen atoms that link the glucose units. At each step along this vector, the geometry of the bimolecular assembly was optimized to give a minimum in the molecular mechanics steric energy. As expected, the energy decreases as the guest molecule enters the cyclodextrin cavity, and again increases as the guest exits from the other side of the cavity. Rotation of the guest within the cavity prior to energy minimization did not result in lower energies; the minimization process found the best rotational orientation of the guest. On the other hand, it was necessary to drive the guest along the vector; the energy minimization process did not pull the guest into an optimal depth of penetration into the cavity. The binding energies calculated at two different dielectric constants were almost identical, indicating that the complex formation is stabilized by dispersive or Van der Waals forces and not electrostatic (dipole-dipole or hydrogen bonding) forces.