Is Retrieval All You Need? Assessment and Emergence of Novelty in Protein Structure Generation

Summary

arXiv:2608.10598v1 Announce Type: new Abstract: Protein backbone generation models are often credited with exploring novel fold space based solely on low full-chain similarity to known proteins, yet this cannot distinguish a genuinely new fold from a novel assembly of known structural units. We first ask whether this granularity mismatch alone explains the reported rates, and introduce the Domain Retrieval Rate (DRR), the fraction of generated backbones for which any constituent domain matches a known domain in CATH S40. Applied to eight backbone generation models spanning diffusion and flow-matching paradigms, DRR finds locally alignable known structure in most outputs, while the fraction containing a substantially covered complete domain is considerably smaller and depends on the scoring convention.