Extended Data Fig. 6: Segments selected for hIAPP fibril inhibitor design.

Three segments of hIAPP, ²¹NNFGAILSS²⁹ (N9S, left panels), ²⁵AILSSTNVG³³ (A9G, middle panels) and ²¹NNFG²⁴ (N4G, right panels), were selected for design of inhibitors of hIAPP fibrils. For each selected segment, the hIAPP structure with the segment highlighted is shown on the top, with the hIAPP structure shown as lines and the segment shown as sticks. Proposed models of the corresponding inhibitor peptides (before adding N-methylation) binding to the hIAPP structures are shown as top views (middle panels) and side views (bottom panels). Notice there are multiple hydrogen bonds between the designed inhibitors and hIAPP fibrils, providing binding affinities for these inhibitors. For the N4G merged inhibitor, the model indicates the orientation-flipped and chirality-reversed N4G has high structural similarity to the original N4G and recaptures all original inter-layer interactions. Hydrogen bonds with distances between 2.3-3.2 Å are shown as black dashed lines.