The hydrophobic effect characterises the thermodynamic signature of amyloid fibril growth

Many proteins have the potential to aggregate into amyloid fibrils, protein polymers associated with a wide range of human disorders such as Alzheimer’s and Parkinson’s disease. The thermodynamic stability of amyloid fibrils, in contrast to that of folded proteins, is not well understood: the balance between entropic and enthalpic terms, including the chain entropy and the hydrophobic effect, are poorly characterised. Using a combination of theory, in vitro experiments, simulations of a coarse-grained protein model and meta-data analysis, we delineate the enthalpic and entropic contributions that dominate amyloid fibril elongation. Our prediction of a characteristic temperature-dependent enthalpic signature is confirmed by the performed calorimetric experiments and a meta-analysis over published data. From these results we are able to define 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.Author summary: Most proteins fold in the cell into stable, compact structures. Nevertheless, many proteins also have the ability to stick together, forming long fibrillar structures that are associated with a wide range of human disorders including Alzheimer’s and Parkinson’s disease. The exact nature of the amyloid-causing stickiness is not well understood, nevertheless amyloid fibrils show some very specific thermodynamic characteristics. Some fibrils even destabilise at low temperatures. In this work we translate hydrophobic theory previously used to model protein folding to fibril formation. We combine this theory with experimental measurements, simulations and meta-data analysis of different types of fibrils. This allowed us to unravel the nature of the stickiness in amyloid fibrils by observing the effect of temperature changes, specifically at low temperatures, on hydrophobicity.