Amyloid β Fibril Elongation by Monomers Involves Disorder at the Tip.

Area of Science:

• Biophysics
• Neuroscience
• Computational Biology

Background:

• Alzheimer's disease pathogenesis involves amyloid-beta (Aβ) peptide aggregation into fibrils.
• Aβ_1-42 fibril growth is proposed to follow a nucleation-elongation mechanism.
• Fibril elongation is often modeled as a two-step 'dock-lock' process.

Purpose of the Study:

• To atomistically characterize the Aβ_1-42 fibril elongation process.
• To elucidate the molecular mechanisms underlying the 'locking' phase of fibril growth.
• To refine the existing 'dock-lock' model of amyloid fibril elongation.

Main Methods:

• Atomistic molecular dynamics simulations of an ordered Aβ42 pentamer.
• Advanced sampling algorithms to efficiently explore conformational space.
• Construction and analysis of a Markov state model from simulation trajectories.

Main Results:

• Identified distinct 'locking' pathways occurring on microsecond timescales.
• Slow steps involve the exchange of hydrophobic contacts (nonnative-native, intra-intermolecular).
• Disordered N-terminal segments of Aβ42 shield lateral interfaces during elongation.

Conclusions:

• The 'locking' step is characterized by significant conformational changes and hydrophobic contact reorganization.
• N-terminal segments play a crucial role in regulating fibril growth.
• Proposed a refined 'dock-lock' model incorporating structural disorder at the growing fibril tip.