The activation barrier for non-enzymatic reactions, which proceed though unstable carbocation (e.g. isopentenyl pyrophosphate isomerase 102 or diterpene synthase 103 ) or carbanion reaction intermediates, is composed mainly of the thermodynamic barrier to formation of the intermediate. We propose that the rate acceleration for these enzymes is achieved by reducing this thermodynamic barrier through a mechanism similar to that documented for TIM, where the substrate binds to an open form of the protein catalyst, which then undergoes a ligand-gated conformational change to create a protein-substrate cage.