Adsorption Free Energy Predicts Amyloid Protein Nucleation Rates

Abstract

Primary nucleation is the fundamental event that initiates the conversion of proteins from their normal physiological forms into pathological amyloid aggregates associated with the onset and development of disorders including systemic amyloidosis, as well as the neurodegenerative conditions Alzheimer's and Parkinson's diseases. It has become apparent that the presence of surfaces can dramatically modulate nucleation. However, the underlying physico-chemical parameters governing this process have been challenging to elucidate, with interfaces in some cases having been found to accelerate aggregation, while in others they can inhibit the kinetics of this process. Here, we show through kinetic analysis that for three different fibril-forming proteins, interfaces affect the aggregation reaction mainly through modulating the primary nucleation step. Moreover, we show through direct measurements of the Gibbs free energy of adsorption, combined with theory and coarse-grained computer simulations, that overall nucleation rates are suppressed at high and at low surface interaction strengths, but significantly enhanced at intermediate strengths, and we verify these regimes experimentally. Taken together, these results provide a quantitative description of the fundamental process which triggers amyloid formation and shed light on the key factors that control this process.

Ganglioside Lipids Inhibit the Aggregation of the Alzheimer’s Related Peptide Amyloid-β

“…Kinetic experiments were thus conducted in systems with different volumes, where wells were filled with a range of 80 -140 µL. 32 This corresponded to a S/V ratio in the range of 0.218 to 0.132 mm −1 .…”

“…In order to probe and monitor the aggregation kinetics of both Aβ42 and Aβ40 with and without the presence of a ganglioside interface, a previously established protocol was followed 32 A 96-well plate (Corning 3881, Half-area) was used. This has a cylindrical shape and thus the cross-sectional surface area remains the same throughout the well, making it ideal to monitor how the surface-to-volume (S/V) ratio, as well as the choice of interface, may affect protein aggregation.…”