Energetic profiling reveals thermodynamic principles underlying amyloid fibril maturation.

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 flexi

SUBMITTER: Duran-Romana R 

PROVIDER: S-EPMC12627711 | biostudies-literature | 2025 Nov

REPOSITORIES: biostudies-literature