The accessible human surfaceome

Abstract

Proteins associated with the extracellular face of the plasma membrane ("surface proteins" or the "surfaceome") are important therapeutic targets because they can direct therapeutics to specific cell types and deliver them into cells. However, experimental and computational databases disagree substantially on which proteins make up the human plasma membrane proteome, and none focus specifically on the set of accessible surface proteins that would be useful for therapeutic applications. Here, we used an agentic LLM pipeline to curate the accessible human surfaceome from literature. To assess performance, we built SurfaceBench, a manually curated benchmark of 147 proteins on which five reference databases frequently disagree. Our LLM triage agent classified surface status more accurately than existing databases and recovered 1,108 candidate surface proteins not present in any of them. On held-out clinical and viral-entry surface targets, the pipeline recovered 98-100% of established surface antigens. A literature-anchored deep-dive pipeline run on over 5,000 candidates then returned 1,783 canonical surface proteins and 1,252 with weaker or context-dependent surface evidence. Each queryable record contains 24 LLM-based annotation fields--including confidence, primary localization, and expression breadth--and seven deterministic structural and topological features. Unlike existing databases, our records trace every claim to the agent's reasoning and to exact quotes from the full-text literature it could access. All records can be browsed in an open-source viewer. These results show that LLMs reasoning over unstructured scientific text can build updatable, bespoke databases that outperform expert-curated resources, although performance remains limited by agent access to full-text literature.