Substrate ionization at this cage is promoted by positioning relevant amino acid side chains so as to provide optimal stabilization of the charged reaction intermediate, relative to the neutral substrate, through electrostatic interactions with catalytic side chains and backbone amides of opposite polarity. The enzymatic reaction may also be promoted through creation of interactions that destabilize the ground state, and which are relieved at the transition state, such as desolvation of the carboxylate side chain of E165, which enhances the basicity of this side chain. This model defines the contribution of participating side chains to catalysis as the effect of the active site side chains forming this catalytic cage on the equilibrium constant for conversion of enzyme-bound substrate to the reaction intermediate (Figure ), and posits that the enzymatic rate accelerations are due mainly to preorganization of polar active-site side chains into positions that provide for optimal stabilization of the enzymatic transition state.