Free-energy perturbation calculations of binding and transition-state energies: hydrolysis of phenyl esters by beta-cyclodextrin

The use of free-energy perturbation simulations for calculating binding and transition-state energies is examined. Reactions of three phenyl esters wi th beta-cyclodextrin are considered. The binding free energies are calculat ed using conventional mutation of the substrate force field from one chemic al structure to another (two-state problem) in water and in the neutral inc lusion complex. For calculation of activation free-energy differences betwe en two substrates the transition states are represented by linear combinati ons of reactant (anionic inclusion complexes) and product (tetrahedral inte rmediate) force fields (four-state problem). The coefficients of this linea r combination are obtained from empirical valence bond simulations of a ref erence substrate. The calculated relative binding and activation energies a re in a good agreement with experimental data. The approximations underlyin g this procedure are discussed. (C) 1999 Elsevier Science B.V. All rights r eserved.