Ground State Destabilization


Ground state destabilization is a thermodynamic concept suggesting that there is an increase in energy in going from one state to another. This concept helps to explain the efficiency of enzyme‐catalysed reactions, as when the substrate binds to the active site of the enzyme there is a destabilization of the substrate. The effect of this destabilization is to reduce the activation energy of a reaction, and so make the catalysis more efficient.

Keywords: destabilization; polarization; conformation; distortion; electrostatics

Figure 1.

Panel (a) represents the activation energy for an uncatalysed unimolecular reaction, Ea‐uni. Panel (b) shows the reaction coordinate diagram for the same process if the enzyme binds to and stabilizes the substrate, transition state and product by the same amount. The activation energy for kcat/Km is reduced but the activation energy for kcat, Ea‐kcat, is necessarily identical to Ea‐uni. The two potential mechanisms out of this conundrum shown by the dashed arrows are either to stabilize the enzyme–transition state complex specifically or destabilize the enzyme–substrate complex.

Figure 2.

A thought experiment allows the quantitation of the different contributions to substrate destabilization. Dihydroxyacetone phosphate bound to the active site of triose phosphate isomerase is shown at the top (adapted from 1TPH in the Brookhaven protein database). The first step in the thought experiment, represented by the diagonal arrow down to the left, is removal of the enzyme to leave the ‘naked substrate’. Two features of the substrate bound to the enzyme have been accentuated: the polarization of the carbonyl π electrons and the length of the C=O bond. In the first step, the electronic polarization is relaxed. In the second step, the bond lengths and arrows are relaxed, and in the third step the substrate is allowed to relax conformationally, as indicated by the four rotations about the heavy‐atom sigma bonds.



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Anderson, Vernon E(Apr 2001) Ground State Destabilization. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1038/npg.els.0000625]