Destabilization of Helix III Initiates Early Serum Amyloid A Misfolding by Exposing Its Amyloidogenic Core.

ABSTRACT: Serum amyloid A (SAA) is the principal precursor of AA amyloidosis, yet the early molecular steps that trigger its pathological misfolding remain unclear. Here, we combine harmonic linear discriminant analysis (HLDA) and parallel-tempering metadynamics (PT-MetaD) to dissect the earliest conformational transitions of the disease-relevant SAA_1-76 fragment. By constructing an optimized one-dimensional collective variable (sHLDA) from interhelix contacts and helical root-mean-square deviations, we perform 4 μs of enhanced sampling across 79 replicas (300-450 K). Free-energy surfaces reveal a misfolding trajectory where helix III destabilizes first, preceding loss of helices II and I while global compactness persists. Solvent-accessible surface-area analysis reveals transient exposur

SUBMITTER: Nadwa H 

PROVIDER: S-EPMC12746452 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature