TTDesign: A Test-Time Design Paradigm for Protein Inverse Folding

Protein language models (PLMs) have advanced the development of protein inverse folding, which aims to design amino acid sequences that fold into a target backbone structure. However, their strong generalization capabilities do not always translate into effective designs for individual target structures. In this work, we propose TTDesign, a novel test-time design paradigm for protein inverse folding that tailors sequence designs to each target structure without requiring any model parameter updates. TTDesign establishes a self-optimization loop with sequence-structure consistency as its guiding objective, iteratively refining sequence designs through structural feedback. Furthermore, TTDesign incorporates a retrieval augmentation mechanism to enhance this process with external protein knowledge. Extensive experiments on CATH v4.2 demonstrate that TTDesign outperforms all baselines in sequence-structure consistency, achieving an average scTM-score of 0.835 compared with 0.802 for the strongest baseline. TTDesign also achieves the best performance on the TS50 benchmark, demonstrating the strong generalization ability of TTDesign.