Does AF3’s reverse docking failure occur for other ligand–protein interactions?

Ascertain whether the “reverse docking” failure mode observed in AlphaFold 3 predictions of CD47–antibody complexes also arises when AlphaFold 3 predicts other types of ligand–protein complex interactions beyond CD47–antibody systems.

Background

The study identifies a recurring failure mode in AlphaFold 3 (AF3) for certain CD47–antibody complexes, termed “reverse docking,” where the antibody and antigen are docked in the opposite orientation relative to the true binding site while sometimes receiving high confidence scores (ipTM, pTM).

After demonstrating and statistically validating this phenomenon for D2510 and reproducing it for D2523, the authors note an open question regarding whether this failure mode generalizes to other classes of ligand–protein interactions predicted by AF3, emphasizing the need for further experiments.