Fig. 1: Structural assessment of IAPP intermediate protofilaments.

A Graphical representation of amyloid fibrils formed by the S20G IAPP mutant⁴⁰. Following the formation of an early intermediate (shown in green), two separate structural lineages are generated as kinetics of aggregation progress (L- and C-lineage). In each structure, colored protofilaments represent the core structural elements that define the fibril polymorph, while grey protofilaments denote later-added peripheral elements that contribute less to the overall stability. B Total stability measurements of individual protofilaments across the L- and C-lineages. Each dot represents a single protofilament, with horizontal lines indicating group means. C Distribution of per-residue folding energies (ΔG) across core protofilaments of the L- (right) and C-lineages (left). Dotted lines indicate the threshold for splitting between stabilizing and destabilizing residue energies. D Backbone hydrogen-bond energies for stabilizing (ΔG < 0; cyan) versus destabilizing (ΔG > 0; green) residues across all core protofilaments of L- (top) and C-lineages (bottom). Stabilizing residues consistently exhibit more favorable hydrogen-bond energetics. Notched box plots with outliers represent median values with the lower and upper hinges corresponding to the 25th and 75th percentiles and whiskers representing non-outlier minimum and maximum values. Statistical comparisons were performed using unpaired two-tailed t-test (n = 1415/1407 destabilizing and n = 1185/1013 stabilizing in L-lineage/C-lineage). E–H Distribution of per-residue contributions to (E) backbone H-bonds, F van der Waals interactions, G solvation energies, as well as (H) total side-chain burial values across core protofilaments of the L- (top) and C-lineages (bottom). Each density curve represents a single protofilament core. All plots are color-coded as in A. Source data are provided as a Source Data file.