ProtBLIP2-SST: Protein Function Prediction via BLIP2 with Sequence, Structure, and Text

Abstract

Protein function prediction traditionally relies on structured gene ontology (GO) labels or multi-label classifiers. However, these labels or classifiers cannot flexibly describe molecular function, biological process, cellular component, and free-text functional narratives in a single output. In comparison, generation-based approaches offer an intuitive paradigm for flexible free-text protein annotation, with large language models (LLMs) as a representative method for protein-text modeling. Recent efforts on utilizing LLMs for protein semantic understanding and annotation generation have adopted sequence-only encoding or sequence-text contrastive alignment paradigms, yet without explicit consideration of three-dimensional structural information. To address these limitations in current protein function prediction methods, we present ProtBLIP2-SST, a two-stage framework built on the BLIP2 model architecture that bridges protein sequence, structure, and text for open-ended protein functional caption generation. Specifically, we first integrate sequence and structure information through SaProt, a protein language model (PLM) with a structure-aware vocabulary that fuses residue tokens with Foldseek-derived 3Di structural tokens. To empower the LLM to understand protein semantics, we employ a Q-Former (a querying transformer in BLIP2) with learnable query tokens as the cross-modal projector to align protein features from the frozen SaProt encoder and text features from a frozen BiomedBERT via protein–text contrasting, protein–text matching, and protein captioning objectives. After alignment, the protein features are linearly projected and prepended to the prompt embeddings of the LLM for protein captioning fine-tuning with LoRA. Trained on 441k protein–text pairs from Swiss-Prot with corresponding structures from the AlphaFold Database, our ProtBLIP2-SST outperforms sequence-only and sequence-text alignment baselines on protein captioning metrics, with ablation studies demonstrating the effectiveness of integrating structure with sequence information for improved protein understanding. Through a unified two-stage alignment-and-generation pipeline, ProtBLIP2-SST integrates protein sequence and structural information, overcomes the rigidity of traditional GO-centric classification, generating open-ended captions that jointly describe molecular function, subcellular location, and homology context in one single output.