Many proteins have the potential to aggregate into amyloid fibrils, which are associated with a wide range of human disorders including Alzheimers and Parkinsons 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.
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