The hydrophobic effect characterises the thermodynamic signature of amyloid fibril growth

Abstract

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.

Role of alpha-Synuclein in Cell Biology: A Hypothesis

“…Consistent with this assumption, in in vitro studies -synuclein fibrils are noted to be unusually heat labile [10][11] . To maintain functional stoichiometry, the dynamic steady state level of -synuclein at the nerve terminus is coupled to efflux of non-functional fibrils through scavenging activities and influx of freshly synthesised monomers (not shown in the figure).…”

The polyphenolic phytoalexin polydatin inhibits amyloid aggregation of recombinant human prion protein

“…Previous studies have reported the importance of hydrophobicity and aromaticity in amyloid assembly and brillation. [33][34][35][36] The subdued hydrophobicity in presence of polydatin further validates its potential to be used as a prion intervening scaffold and therapeutic agent which may help in abrogating the amyloid assembly of aggregating monomers by binding to its aromatic and hydrophobic patches.…”

Evaluation of FRET X for Single-Molecule Protein Fingerprinting

“…We set out to evaluate the performance of our method for targeted proteomics, based on simulations. For this we sought to identify the different spliceoforms of the apoptosis regulator Bcl-2 (UniProt ID: Q07817), which are potential biomarkers for cancer 23 and are likely to produce different fingerprints. While BCL-XL is an anti-apoptotic regulator, both BCL-XS and BCL-Xb are pro-apoptotic factors.…”

“…Despite their simplicity, past investigations have shown that lattice models can reproduce native protein folding behavior. [19][20][21][22][23] The attachment of DNA tags to selected residues, as required to accurately model our approach, has not previously been included in lattice models. The precise effect of DNA tags on protein structure is unclear.…”