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bioRxiv · 10.64898/2026.01.30.702803

The monomeric conformational ensembles of Aβ40 and Aβ42 encode their differential amyloid aggregation propensity

Cadenelli, I.·Ciccolo, A.·Tagliabue, A.·Rossi, G.·Conti Nibali, V.·Bochicchio, D.
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Abstract

A{beta}40 and A{beta}42 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, A{beta}42 shows systematically higher {beta}-structure propensity, especially in the C-terminal region, and samples more extended conformations with higher hydrophobic exposure compared to A{beta}40. 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 A{beta}42s distinct aggregation behavior.

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Cadenelli, I., Ciccolo, A., Tagliabue, A., Rossi, G., Conti Nibali, V., Bochicchio, D.. 2026-02-02. The monomeric conformational ensembles of Aβ40 and Aβ42 encode their differential amyloid aggregation propensity. https://doi.org/10.64898/2026.01.30.702803

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