Energetic profiling reveals thermodynamic principles underlying amyloid fibril maturation

Ramon Duran-Romaña, Joost Schymkowitz (), Frederic Rousseau () and Nikolaos Louros ()
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Ramon Duran-Romaña: Herestraat 49
Joost Schymkowitz: Herestraat 49
Frederic Rousseau: Herestraat 49
Nikolaos Louros: Herestraat 49

Nature Communications, 2025, vol. 16, issue 1, 1-13

Abstract: Abstract Amyloid fibrils adopt diverse structural polymorphs linked to disease-specific phenotypes, but the thermodynamic principles guiding their formation and maturation remain unclear. Here, we apply energetic profiling to structural time series from cryo-EM datasets of IAPP, tau, and α-synuclein to decode the principles governing fibril maturation and polymorphic divergence. By mapping residue-level free energy contributions across experimentally resolved assembly pathways, we reconstruct their maturation trajectories and find that amyloid assembly is anchored by aggregation-prone regions that serve as sequence-encoded stabilizing motifs. As assembly progresses, these motifs are reorganized and expanded, while additional regions introduce structural frustration that enables conformational flexibility. Environmental cofactors such as metal ions or polyanions are observed in association with regions of structural remodeling, where they may act to compensate for otherwise energetically strained conformations. This framework offers mechanistic insight into how distinct polymorphs arise from a common sequence and mature through both intrinsic and extrinsic thermodynamic influences.

Date: 2025
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DOI: 10.1038/s41467-025-65035-0

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