CALCULATIONS OF ASSOCIATION FREE-ENERGIES - SEPARATION OF ELECTROSTATIC AND HYDROPHOBIC CONTRIBUTIONS

Relative association free energies of six sulfonamide/beta-cyclodextrin inclusion complexes are calculated using a thermodynamic cycle that separates these reactions into purely electrostatic and hydrophobic components. Electrostatic free energy differences are calculated using slow-growth thermodynamic integration, and hydrophobic free energy differences are obtained using an empirical relationship based on the difference between the solvent-accessible surface areas of the solute species in their associated and dissociated states. Two sets of calculations are performed: one in which the model system includes solvent, and the other in which the model system does not include solvent. The calculations performed with the solvated model are accurate to roughly +/-1.5 kcal/mol, and correctly select the preferred of the two possible binding conformations in three out of the four cases examined.