The Monomeric Conformational Ensembles of Aβ40 and Aβ42 Encode Their Differential Amyloid Aggregation Propensity

Area of Science:

• Biochemistry
• Molecular Biology
• Computational Chemistry

Background:

• Amyloid beta (Aβ) peptides, specifically Aβ40 and Aβ42, exhibit distinct aggregation and toxicity profiles.
• The underlying reasons for these differences, particularly at the monomer level, remain incompletely understood.
• Understanding monomeric differences is crucial for elucidating the mechanisms of amyloid formation.

Purpose of the Study:

• To compare the monomeric conformational ensembles of Aβ40 and Aβ42 under identical conditions.
• To investigate whether sequence-encoded monomer preferences dictate differential amyloidogenicity.
• To identify monomer-level determinants contributing to Aβ42's distinct aggregation behavior.

Main Methods:

• Extensive all-atom molecular dynamics simulations in explicit solvent.
• Well-tempered metadynamics for enhanced sampling of conformational space.
• Tailored consensus cluster analysis to characterize monomeric ensembles.

Main Results:

• Both Aβ40 and Aβ42 monomers populate broad, coil-like conformational distributions.
• Aβ42 demonstrates a systematically higher propensity for β-structure, particularly in the C-terminal region.
• Aβ42 samples more extended conformations with increased hydrophobic exposure compared to Aβ40.

Conclusions:

• Monomer conformational preferences are mechanistically linked to the differential amyloidogenicity of Aβ isoforms.
• Sequence-encoded properties at the monomer level significantly influence aggregation propensity.
• These findings highlight key monomer-level determinants responsible for Aβ42's unique aggregation characteristics.