PRISM: Enhancing PRotein Inverse Folding through Fine- Grained Retrieval on Structure-Sequence Multimodal Representations

ICLR 2026 Conference Submission17072 Authors

Keywords: Retrieval Augmented Generation, Protein Language Modeling, Protein Inverse Folding, Protein Sequence Design, Multimodal Representation

TL;DR: We present PRISM, a multimodal retrieval-augmented generation framework that enhances protein inverse folding by dynamically integrating fine-grained structure-sequence multimodal representations from a larger protein database.

Abstract:

Designing protein sequences that fold into a target three-dimensional structure, known as the inverse folding problem, is central to protein engineering but remains challenging due to the vast sequence space and the importance of local structural constraints. Existing deep learning approaches achieve strong recovery rates, yet they lack explicit mechanisms to reuse fine-grained structure-sequence patterns that are conserved across natural proteins.
We present PRISM, a multimodal retrieval-augmented generation framework for inverse folding that retrieves fine-grained representations of potential motifs from known proteins and integrates them with a hybrid self-cross attention decoder. PRISM is formulated as a latent-variable probabilistic model and implemented with an efficient approximation, combining theoretical grounding with practical scalability.
Across five benchmarks (CATH-4.2, TS50, TS500, CAMEO 2022, and the PDB date split), PRISM establishes new state of the art in both perplexity and amino acid recovery, while also improving foldability metrics (RMSD, TM-score, pLDDT), demonstrating that fine-grained multimodal retrieval is a powerful and efficient paradigm for protein sequence design.

Primary Area: applications to physical sciences (physics, chemistry, biology, etc.)

Submission Number: 17072