TY - JOUR
T1 - The hydrophobic effect characterises the thermodynamic signature of amyloid fibril growth
AU - Gils, Juami Hermine Mariama van
AU - Dijk, Erik van
AU - Peduzzo, Alessia
AU - Hofmann, Alexander
AU - Vettore, Nicola
AU - Schützmann, Marie P
AU - Groth, Georg
AU - Mouhib, Halima
AU - Otzen, Daniel E
AU - Buell, Alexander K
AU - Abeln, S.
PY - 2020/5/4
Y1 - 2020/5/4
N2 - 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.
AB - 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.
UR - https://research.vu.nl/en/publications/c5d5d3d6-4a8f-4860-8084-29e252132669
U2 - 10.1371/journal.pcbi.1007767
DO - 10.1371/journal.pcbi.1007767
M3 - Article
C2 - 32365068
SN - 1553-734X
VL - 16
JO - PLoS Computational Biology
JF - PLoS Computational Biology
IS - 5
ER -