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

ABSTRACT: 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

SUBMITTER: Rodriguez RA 

PROVIDER: S-EPMC5911799 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature