Structural analysis of host-guest systems. Methyl-substituted phenols in β-cyclodextrin

Complexation trajectories and the variation of induced circular dichroism are calculated for the docking of phenol and 2,4,6-trimethyl-phenol with β-cyclodextrin. The results are compared to experimental chirality data to elucidate the mechanism of nonspecific molecular recognition processes in aqueous solution. Large geometrical changes along nearly isoenergetic Dynamic Monte Carlo trajectories show the conformational flexibility of such host-guest systems. This proves diffuse intermolecular interactions, van der Waals or electrostatic in nature, as the main contributions to the binding energy. The number and position of the methyl substituents of the guest reduces the complexity of the conformational space as the guest's position becomes fixed by steric constraints. The solvation free energy is calculated from the solvent accessible surface area weighted by respective atomic solvation parameters. Considering the solvation term in the dynamic simulations restricts the conformational flexibility of the macromolecular system. The relative importance of various contributions to the solvation energy is discussed and it is shown that those terms arising from the interaction of hydrophobic groups with the aqueous environment are essential for the determination of the complex structure. Considering these terms in the dynamic simulation model, the sign and strength of the calculated rotatory strength is in perfect agreement with induced circular dichroism obtained from experimentally determined averaged spectra. The results demonstrate the accuracy of the geometrical properties of host-guest systems obtained from these simulations.