ProCyon: A multimodal foundation model for protein phenotypes

Abstract

Understanding the roles of human proteins remains a major challenge, with approximately 20% of human proteins lacking known functions and more than 40% missing context-specific functional insights. Even well-annotated proteins are often poorly characterized in diverse biological contexts, disease states, and perturbations. We present ProCyon, a foundation model for modeling, generating, and predicting protein phenotypes across five interrelated knowledge domains: molecular functions, therapeutic mechanisms, disease associations, functional protein domains, and molecular interactions. To support this, we created ProCyon-INSTRUCT, a dataset of 33 million protein phenotype instructions, representing a comprehensive resource for multiscale protein phenotypes. By co-training a large language model with multimodal molecular encoders, ProCyonintegrates phenotypic and protein data. A novel architecture and instruction tuning strategy allow ProCyonto process arbitrarily interleaved protein-and-phenotype inputs, achieve zero-shot task transfer, and generate free- form text phenotypes interleaved with retrieved protein sequence, structure, and drug modalities in a single unified model. ProCyonachieves strong performance against single-modality models, multimodal models such as ESM3, as well as text-only LLMs on dozens of benchmarking tasks such as contextual protein retrieval and question answering. We extensively evaluate ProCyonfor biological applications, including identifying protein domains that bind small molecule drugs, predicting peptide binding with enzymes, and assessing the functional impact of Alzheimer’s disease mutations. ProCyonenables conditional retrieval of proteins linked to small molecules through complementary mechanisms of action. It generates candidate phenotypes for under-characterized proteins recently implicated in Parkinson’s disease, facilitating hypothesis generation for poorly understood proteins and biological processes. ProCyonpaves the way toward an effective, general solution for functional