A two-step reversible-irreversible model can account for a negative activation energy in an Arrhenius plot.

Arrhenius plots of the rate of inactivation (killing) of mammalian cells and Drosophila embryos have "apparent negative" activation energies at low temperatures. This can be explained by assuming that the rate-limiting event resulting in killing is a two-step process or mechanism, where the first step is reversible and the second irreversible. Two examples, consistent with this model, are suggested as possible mechanisms of hypothermic killing: (i) a membrane lipid liquid crystalline-to-gel transition followed by a metabolic block or event which kills the cell and (ii) cold denaturation of a protein followed by protein aggregation.