Abstract
Homology is a key concept underpinning the comparison of sequences across organisms. Sequence-level homology is based on a statistical framework optimized over decades of work. Recently, computational protein structure prediction has enabled large-scale homology inference beyond the limits of accurate sequence alignment. In this regime, it is possible to observe nearly identical protein structures lacking detectable sequence similarity. In the absence of a robust statistical framework for structure comparison, it is largely assumed similar structures are homologous. However, it is conceivable that matching structures could arise through convergent evolution, resulting in analogous proteins without shared ancestry. Large databases of predicted structures offer a means of determining whether analogs are present among structure matches. Here, I find that a small subset (∼2.6%) of Foldseek clusters lack sequence-level support for homology, including ∼1% of strong structure matches with template modeling score ≥ 0.5. This result by itself does not imply these structure pairs are nonhomologous, since their sequences could have diverged beyond the limits of recognition. Yet, strong matches without sequence-level support for homology are enriched in structures with predicted repeats that could induce spurious matches. Some of these structural repeats are underpinned by sequence-level tandem repeats in both matching structures. I show that many of these tandem repeat units have genealogies inconsistent with their corresponding structures sharing a common ancestor, implying these highly similar structure pairs are analogous rather than homologous. This result suggests caution is warranted when inferring homology from structural resemblance alone in the absence of sequence-level support for homology.