One is by shifting the minima of the VB parabolas relative to each other (an example of the Hammond postulate, which would give rise to an LFER such as those shown in Figure ). The alternative involves altering the reorganization energy of the reaction, thus shifting the relative positions of the two diabatic states (an example of the Principle of Least Nuclear Motion, for more detailed discussion we refer the reader to ref. ), without necessarily any accompanying change in the overall reaction driving force. Hence, one would expect that EVB calculations should detect LFER (Figure ) in other cases where there is a strong imperative for stabilization of an enzyme-bound reaction intermediate relative to the intermediate in water. Breakdowns of these LFER might be observed for amino acid substitutions that cause increases in the reaction activation barrier ∆G ‡ , without affecting the reaction driving force ∆G 0 . For example, amino acid substitutions that cause significant increases in the distance separating the enzymic base from the bound carbon acid substrate, may cause increases in ∆G ‡ without changing the relative stability of the enzyme-bound substrate and reaction intermediate. In such a situation, the EVB simulations would still pick up the impact of these substitutions on the catalytic effect of the enzyme, without producing an LFER. Therefore, an LFER is not necessarily the expected outcome from performing EVB simulations.