Characterizing amyloid-beta protein misfolding from molecular dynamics simulations with explicit water

Area of Science:

• Biochemistry
• Molecular Biology
• Neuroscience

Background:

• Alzheimer's disease (AD) is characterized by extracellular amyloid-beta (Aβ) protein deposition.
• Limited understanding of Aβ protein aggregate formation during the lag phase in extracellular environments.

Purpose of the Study:

• To characterize the aggregation-prone structure (APS) of monomeric amyloid-beta 42 (Aβ42).
• To elucidate early conformational transitions in Aβ42 misfolding during the lag phase.
• To propose a mechanism for Aβ42 aggregation into fibrils.

Main Methods:

• Multiple all-atom molecular dynamics simulations of Aβ42 in explicit water.
• Analysis of early sequential conformational transitions and structural features.

Main Results:

• Identified the APS of Aβ42 monomer, correlating nonlocal backbone H-bond formation with hydrophobic side-chain exposure.
• Provided insights into the higher aggregation propensity of Aβ42 compared to Aβ40.
• Proposed a plausible aggregation pathway from APS to fibril formation.

Conclusions:

• The characterized APS and early transitions offer new perspectives on Aβ42 aggregation in Alzheimer's disease.
• Simulation findings align with experimental data (NMR) and suggest driving forces for Aβ42 aggregation.
• Elucidates the structural origins of Aβ42 aggregation contributing to AD pathogenesis.