Rescuing true protein binders from AI hallucinations via zero-shot, ensemble-driven statistical physics scoring (opens in new tab)

The advancement of deep generative models has facilitated de novo protein and antibody design, yet translation to experimental success is hindered by a high generation rate of structural decoys. Current affinity predictors and standard structural confidence metrics fail to reliably distinguish these AI hallucinations from true binders. Here, we present Sipobe-PPA, an affinity ranking framework that conceptualizes interacting protein interfaces as pseudo-ligands, evaluating them through an AI-...