Event Embedding of Protein Networks : Compositional Learning of Biological Function

Networks describe systems in biology and beyond, from protein interactions and social relationships to power grids and citation records. Reasoning about such systems requires understanding their structure: which elements are central, which connections bridge separate communities, and how it changes when elements are removed. Although large language models (LLMs) excel at natural language, they struggle with such questions when networks are given as edge lists, sentences or measurement tables, because their structural meaning must be inferred. Here we introduce BioGlyph, which compiles network topology into an interpretable and transferable language of structural roles. BioGlyph combines graph partitioning and structural measurements to identify roles such as hubs, community cores and cross-community connectors, and fixed rules to translate them into a universal vocabulary. The representation describes each element through its structural role, supporting evidence and semantic consequences, leaving both the network and the LLM unchanged. Across twenty networks spanning five domains, BioGlyph substantially improves open LLMs' ability to answer structural reasoning questions, outperforming edge-based, numerical and learned representations by up to 26 percentage points in system accuracy. Ablations show that the gain comes from explicitly encoding structural roles in semantically interpretable terms. The gain is more prominent in dense, community-structured networks and diminishes in sparse networks whose topology is more readily inferred from text. In a budding-yeast protein-interaction network, BioGlyph exposes biological organization: cross-community connectors are enriched for essential genes, whereas peripheral proteins are depleted. BioGlyph thus provides an interpretable representation for both language models and scientists to reason about network structure.

Protein language models produce rich per-residue representations, but the sequence embeddings obtained by mean-pooling them are never trained to place related proteins near one another, so the geometry that retrieval, clustering and nearest-neighbor transfer depend on is never optimized. We present ProtSent, a contrastive post-training framework that supervises a protein language model with three types of biological relation at once, Pfam family co-membership, AlphaFold DB structural clusters and STRING interactions, and with deep mutational scanning fitness ordering as an optional fourth. It needs no structure at training or inference, trains on corpora filtered at 40% sequence identity against the benchmark test sets they most resemble, and is applied to ESM-2 (35M and 150M parameters) and ESM-C (300M). Post-training makes structural family membership recoverable from the frozen embedding without a trained readout: on SCOPe-40, the adjusted Rand index of the 35M model rises from 0.054 (near chance) to 0.507, and family retrieval gains +0.185, +0.190 and +0.424 Recall@1 over the three frozen backbones, with paired bootstrap intervals excluding zero. On the CATH midnight-zone benchmark, homologous-superfamily accuracy rises from 40.7% to 56.7% at 35M and from 43.3% to 62.7% at 150M, more than the 12 points a CATH-supervised model gains over its own base. Against a maximally sensitive HMMER search, alignment keeps the best single hit at both ESM-2 scales, but the embedding leads at ranking depth (MAP 0.705 against 0.607 at 150M) and returns a ranking for every query, including those where alignment finds none. Under a trained linear probe, however, the same embeddings fall below the untuned backbone, as do structure-distilled embeddings against theirs, so the gain in neighborhood structure comes at a cost in linear-probe accuracy. Code and models: https://github.com/oriel9p/ProtSent

Protein language models often take into consideration the alignment between a protein sequence and its textual description. However, they do not take structural information into consideration. Traditional methods treat sequence and structure separately, limiting the ability to exploit the alignment between the structure and protein sequence embeddings. In this paper, we introduce a sequence structure contrastive alignment framework, which learns a shared embedding space where proteins are represented consistently across modalities. By training on large-scale pairs of sequences and experimentally resolved or predicted structures, the model maximizes agreement between matched sequence structure pairs while pushing apart unrelated pairs. This alignment enables cross-modal retrieval (e.g., finding structural neighbors given a sequence), improves downstream prediction tasks such as function annotation and stability estimation, and provides interpretable links between sequence variation and structural organization. Our results demonstrate that contrastive learning can serve as a powerful bridge between protein sequences and structures, offering a unified representation for understanding and engineering proteins.