Backbone: RFdiffusion, 1583 scaffolds, 6 helical campaigns (e2_groove/helix/loop3/broad/loop3_znrep/helical_core), binder length 50-80 AA, E2-surface hotspots only (res 73-97), Zn coordination face excluded.

Sequence: LigandMPNN --model_type ligand_mpnn, T=0.2, 16 seqs/backbone, biases: A:-3.0 W:+2.0 Y:+1.5 F:+1.0 C:-999.0.

Filters: Ala<20%, charge [-5,+5], aromatics>=3%, unique AA>=14. AF2 monomer pLDDT>=85.

Validation: AF3 Server (1136 designs, 40 batches), ipSAE_d0chn scoring. 183 hits (>=0.5), 75 elite (>=0.8).

Selection gates: no clash, disorder<=10%, binder+target pTM>=0.70, AF2 pLDDT>=88. 672 passed -> 522 deduped -> top 100 by ipSAE + diversity.

Auxiliary: ESM2-650M pseudo-perplexity for batch prioritization.

Hardware: NVIDIA GB10 Blackwell, CUDA 12.8.