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.