  Many proteins have the potential to aggregate into amyloid fibrils, which are
associated with a wide range of human disorders including Alzheimer's and
Parkinson's disease. In contrast to that of folded proteins, the thermodynamic
stability of amyloid fibrils is not well understood: specifically the balance
between entropic and enthalpic terms, including the chain entropy and the
hydrophobic effect, are poorly characterised. Using simulations of a
coarse-grained protein model we delineate the enthalpic and entropic
contributions dominating amyloid fibril elongation, predicting a characteristic
temperature-dependent enthalpic signature. We confirm this thermodynamic
signature by performing calorimetric experiments and a meta-analysis over
published data. From these results, we can also elucidate the necessary
conditions to observe cold denaturation of amyloid fibrils. Overall, we show
that amyloid fibril elongation is associated with a negative heat capacity, the
magnitude of which correlates closely with the hydrophobic surface area that is
buried upon fibril formation, highlighting the importance of hydrophobicity for
fibril stability.
