Thermodynamics of Amyloid-β Fibril Elongation: Atomistic Details of the Transition State

Amyloid-β (Aβ) fibrils and plaques are one of the hallmarks of Alzheimer's disease. While the kinetics of fibrillar growth of Aβ have been extensively studied, several vital questions remain. In particular, the atomistic origins of the Arrhenius barrier observed in experiments have not been elucidated. Employing the familiar thermodynamic integration method, we have directly simulated the dissociation of an Aβ (15-40) (D23N mutant) peptide from the surface of a filament along its most probable path (MPP) using all-atom molecular dynamics. This allows for a direct calculation of the free energy profile along the MPP, revealing a multipeak energetic barrier between the free peptide state and the aggregated state. By definition of the MPP, this simulated unbinding process represents the reverse of the physical elongation pathway, allowing us to draw biophysically relevant conclusions from the simulation data. Analyzing the detailed atomistic interactions along the MPP, we identify the atomistic origins of these peaks as resulting from the dock-lock mechanism of filament elongation. Careful analysis of the dynamics of filament elongation could prove key to the development of novel therapeutic strategies for amyloid-related diseases.