Native-to-fibril structural remodelling reveals an amyloid-selective transthyretin epitope for AI-guided binder design

Abstract Transthyretin (TTR) amyloidosis involves conversion of the native tetramer into cross-$\beta$ fibrils, creating potential targets for conformation-selective binders. Full-assembly solvent-accessibility analysis of 30 patient-derived fibril structures, spanning wild-type TTR and ten hereditary variants, identifies increased exposure of an N-terminal region adjacent to Cys10. Using a common normalisation reference, mean relative solvent accessibility for residues 11--15 is 0.089 in native TTR and at least 0.168 in fibrils. Modification mapping, saturation-mutagenesis stability predictions and steric PTM models provide molecular context. BoltzGen and RFAntibody generate candidate binders, and sequence-only Boltz-2 counter-predictions place selected nanobodies at the Pro11/Met13/Lys15 region in fibril-derived constructs but at distal surfaces in native-state constructs. Vitreous-fibril designs also engage cardiac-fibril constructs, suggesting cross-tissue epitope recognition. These results support structure-guided candidate prioritisation, while fibril geometry, binding affinity and disease-state selectivity require experimental validation.