BioReason-Pro: Advancing Protein Function Prediction with Multimodal Biological Reasoning

Abstract Protein function annotation is fundamental to understanding biological mechanisms, designing therapeutics, and advancing biomedical research. Current computational methods either rely on shallow sequence similarity or treat function prediction as isolated classification tasks, failing to capture the integrative reasoning across sequence, structure, domains, and interactions that expert biologists perform to infer function. We introduce BioReason-Pro, the first multimodal reasoning large language model (LLM) for protein function prediction that integrates protein embeddings with biological context to generate structured reasoning traces. A key input into BioReason-Pro is the set of GO term predictions made by GO-GPT, our autoregressive transformer that captures hierarchical and cross-aspect dependencies of GO terms. BioReason-Pro is trained via supervised fine-tuning on synthetic reasoning traces generated by GPT-5 for over 130K proteins and further optimized through reinforcement learning. It achieves 73.6% F max on GO term prediction and an LLM judge score of 8/10 on functional summaries, substantially outperforming previous methods. Evaluations with human protein experts show that BioReason-Pro annotations are preferred over ground truth UniProt annotations in 79% of cases. Remarkably, BioReason-Pro de novo predicted experimentally confirmed binding partners with per-residue attention localizing to the exact contact residues resolved in cryo-EM structures of those complexes. Together, GO-GPT and BioReason-Pro establish a framework for protein function prediction that combines precise ontology modeling with interpretable biological reasoning.