Cofolding models can place the ligand right while getting the protein conformation wrong
- AlphaFold3, RoseTTAFold3, Boltz-2 and Chai-1 were benchmarked on kinases and Class A GPCRs, families whose pharmacology depends on defined conformational states.
- Only complexes released after all four models' training cutoffs were used, plus one earlier control structure, to give a prospective test.
- Correct ligand placement turned out to be systematically decoupled from accurate prediction of the surrounding protein conformation.
💡 Points
For anyone docking into cofolded poses, this is the warning label: a plausible ligand pose does not mean the DFG state or GPCR activation state is right. That matters most for type II kinase inhibitors and biased GPCR ligands, where the conformation is the whole point. I'd treat cofolded structures as hypotheses to validate against known conformational markers before using them for SAR design.