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

Aβ40 and Aβ42 peptides differ by just two C-terminal residues, yet they display strikingly different aggregation and toxicity profiles. Whether this distinction is already encoded at the monomer level is still under debate. Here, we combine extensive all-atom simulations in explicit solvent, well-tempered metadynamics, and a tailored consensus cluster analysis to compare the monomeric ensembles of the two isoforms under identical conditions. Both peptides populate broad, coil-like conformational distributions; however, Aβ42 shows a systematically higher β-structure propensity, especially in the C-terminal region, and samples more extended conformations with higher hydrophobic exposure compared to Aβ40. These results support a mechanistic link between sequence-encoded monomer conformational preferences and the differential amyloidogenicity of the two isoforms, highlighting monomer-level determinants of Aβ42's distinct aggregation behavior.