Why does fibrillation accelerate at 4 °C rather than proceeding linearly?

The specifics, since they change the answer: fibrillation · 4 °C.

I understand the observation; what I do not understand is the mechanism behind it.

I have read the two review articles that come up first and both assert this without a citation to a primary source.

So what is the mechanism, and how well established is it?

Because temperature enters the rate constant through an exponential, so equal steps in temperature multiply the rate instead of adding to it. Arrhenius puts the rate proportional to exp(−Ea/RT); the working approximation is a doubling per 10 K, which takes 5, 15, 25 and 35 °C to multipliers of 1, 2, 4 and 8. The steps in temperature are equal and the steps in rate are not, and that is the whole of the observation. At 4 °C the same rule gives about 0.9 times the refrigerated rate, and another 10 K would roughly double it again. Ordered beta-sheet assembly, effectively irreversible, and its endpoint is opalescence you can see rather than a peak you can integrate. Ea differs by route, so the ranking of routes changes with temperature too — which is why accelerated data extrapolates badly and why nobody should read a 40 °C study as a fast version of a 5 °C one.

The relevant point is that a mass shift of plus one dalton is deamidation and plus sixteen is oxidation, so degradation is often visible in a mass spectrum if anyone looks.

Light exposure matters for tryptophan-containing sequences and for anything with a chromophore. Amber vials and a closed box are free mitigations.

In practice, oxidation targets methionine, cysteine and tryptophan, adding sixteen daltons per oxygen. It is catalysed by trace metals and promoted by dissolved oxygen and by light.

Deamidation via the succinimide intermediate is well characterised, with sequence-dependent rates highest for asparagine-glycine motifs.

Sequence decides which pathways are even available. Check the residues.

edited 15 Jul 2026 by gradient_slope — corrected a unit error in the worked example