A procedure is described which leads to experimentally based models for the transitionstate structures of enzyme-catalyzed reactions. Substrates for an enzymic reaction are synthesized with isotopically enriched atoms at every position in which bonding changes are anticipated at the enzyme-enforced transition state. Kinetic isotope effects are measured for each atomic substitution and corrected for diminution of the isotope effects from nonchemical steps of the enzymic mechanism. A truncated geometric model of the transition-state structure is fitted to the kinetic isotope effects using bond-energy bondorder vibrational analysis. Full molecularity is restored to the transition state while maintaining the geometry of the bonds which define the transition state. Electronic wave functions are calculated for the substrate and the transition-state molecules. The molecular electrostatic potential energies are defined for the van der Waal surfaces of substrate and transition state and displayed in numerical and color-coded constructs. The electronic differences between substrate and transition state reveal characteristics of the transition state which permits the extraordinary binding affinity of enzyme-transition state interactions. The information has been used to characterize several enzymatic transition states and to design powerfully inhibitory transition-state analogues. Enzymatic examples are provided for the reactions catalyzed by AMP deaminase, nucleoside hydrolase, purine nucleoside phosphorylase, and for several bacterial toxins. The results demonstrate that the combination of experimental, classical, and quantum chemistry approaches is *To whom correspondence should be addressed.