MIRAGE: Measuring Interpolation and Redundancy in Affinity GEneralization

RESUMO

Deep learning now underpins structure-based drug design, from complex and affinity prediction to ligand ranking and pose generation. Recent co-folding models reportedly approach free-energy-perturbation accuracy at far lower cost. Yet standard evaluation, a single held-out correlation or pooled pose-success rate, cannot separate transferable binding principles from repeated exposure to related protein families in public databases, and practical success depends on genuinely novel targets. We introduce MIRAGE (Measuring Interpolation and Redundancy in Affinity GEneralization), a plug-in benchmark treating historical public family support (through 2019) as an explicit variable, applying a family-support axis to affinity and pose prediction via matched strata, family-disjoint controls, ligand-only baselines, and temporal evaluation. Co-folder affinity accuracy rises sharply with family support, while shallow controls that cannot exploit the test family stay flat, large for co-folders and near zero for every family-disjoint or trivial control. For Nesso-1 it survives covariate, conditioning, balancing, and clustering checks; Boltz-2's endpoint is limited by coverage. It localizes to family support rather than ligand chemistry, approaching a level from family identity alone. Rankings reverse on novel families, where a family-disjoint random forest leads both co-folders, significantly vs Nesso-1. On one external low-support target, neither co-folder beats molecular weight, corroborative rather than population-level evidence. gnina shows significant support dependence in rescoring whereas smina does not; MSA-free pose engines show larger gaps than smina redocking. This redundancy-driven inflation differs from conventional leakage. We propose reporting performance across family support plus excess over a support-insensitive baseline, and release MIRAGE as an installable benchmark and dataset.