Contrastive learning unites sequence and structure in a global representation of protein space.

Establishing a coherent mapping of the relationships among all known proteins is crucial for elucidating processes of protein emergence and evolution. Yet the capacity to fully capture relationships of protein similarity is complicated by the nonstraightforward interplay between sequence and structure; indeed, proteins with unrelated sequences can adopt similar structures, and, conversely, proteins with similar or identical sequences can manifest radically different structures. Here, we introduce Contrastive Learning Sequence-Structure (CLSS), a contrastive protein language model (PLM) trained to coembed sequence and structure information in a self-supervised manner, facilitating a holistic representation of protein relatedness. CLSS represents the structures and sequences of full domains and domain subsequences as vectors in the same high-dimensional latent space. We show that this approach yields meaningful shared representations, which recapitulate the extensive structure- and sequence-based knowledge encoded in human-curated hierarchical protein classification systems (ECOD and CATH). Moreover, the representations generated by CLSS outperform those generated by alternative state-of-the-art PLMs in downstream classification tasks. Notably, we show that even the far larger space of domain subsequences is successfully coembedded, establishing a PLM tailored to these evolutionarily meaningful objects. CLSS embeddings produce informative representations of the protein universe without further downstream processing, as we demonstrate by analyzing preferential associations between protein architectures and ligand types across protein space.