Extended Data Fig. 2: The top views of single transmembrane helices binding poses and probe binding pose distribution analysis respect to different targeting sites.

a-h, Models are super-positioned with the D1R chain as reference, overlayed with the probe point cloud. CD69 in CD69-S1PR1 complex (PDB: 8G94²⁰) (a). MRAP1 in MRAP1-MC2R complex (PDB: 8GY7²¹) (b). RAMP1 in CGRPR (PDB: 6E3Y²²) (c). RAMP1 in AMY1R (PDB: 7TYF²³) (d). RAMP2 in AMY2R (PDB: 7TYY²³) (e). RAMP2 in AM1R (PDB: 6UUN²⁴) (f). RAMP3 in AMY3R (PDB: 7TZF²³) (g). RAMP3 in AM2R (PDB: 6UVA²⁴) (h). i-k, Probe point clouds with different TMD targeting sites (TM1/2/4, TM3/4/5, TM5/6) as the RFDiffusion binder protocol condition, colored by normalized density. Each point cloud is roughly divided into three distinct sub-clouds: TM1/2/4, TM3/4/5 and TM5/6/7. The number near the sub-cloud is calculated as the number of related predicted models contributing to this sub-cloud. The color of a point represents the normalized density value of the grid it belongs to. Density normalization is calculated individually for each point cloud. Probe point clouds were generated with starting scaffolds targeting TM1/2/4 (i), targeting TM3/4/5 (j) and targeting TM5/6 (k).