Examining the Ensembles of Amyloid-β Monomer Variants and Their Propensities to Form Fibers Using an Energy Landscape...

Area of Science:

• Biophysics
• Computational Biology
• Neuroscience

Background:

• Amyloid-beta (Aβ) monomers, particularly Aβ-40 and Aβ-42, are intrinsically disordered peptides implicated in Alzheimer's disease (AD) pathogenesis.
• Aβ-42 is more prone to forming pathological aggregates than Aβ-40, despite its lower natural abundance.
• Specific single-point mutations in Aβ are associated with early-onset forms of AD.

Purpose of the Study:

• To analyze the structural and energetic properties of normal Aβ-40 and Aβ-42 monomers, as well as six disease-associated mutants.
• To evaluate the utility of the energy landscape visualization method (ELViM) for studying intrinsically disordered proteins (IDPs).
• To identify amino acid contacts that characterize different monomer ensembles and their aggregation propensities.

Main Methods:

• Coarse-grained associative-memory, water-mediated, structure and energy model (AWSEM) simulations were performed on Aβ-40, Aβ-42, and six mutant variants.
• The energy landscape visualization method (ELViM), a reaction-coordinate-free approach, was employed to analyze the simulation data.
• ELViM was used to explore the frustrated energy landscapes characteristic of IDPs.

Main Results:

• ELViM effectively differentiated between monomer ensembles of Aβ variants that form fibers rapidly and those that do not.
• The method successfully delineated specific amino acid contacts associated with each distinct monomer ensemble.
• Simulation results provided insights into the behavior of intrinsically disordered Aβ monomers.

Conclusions:

• ELViM is a powerful tool for analyzing the conformational ensembles of intrinsically disordered proteins, including amyloid-beta.
• The study elucidates the molecular basis for differential aggregation propensities among Aβ variants.
• Findings contribute to understanding the structural underpinnings of Alzheimer's disease.