Cross-Chirality Generalization by Axial Vectors for Hetero-Chiral Protein-Peptide Interaction Design

D-peptide binders targeting L-proteins have promising therapeutic potential. Despite rapid advances in machine learning-based target-conditioned peptide design, generating D-peptide binders remains largely unexplored. In this work, we show that by injecting axial features to E(3)-equivariant (polar) vector features, it is feasible to achieve cross-chirality generalization from homo-chiral (L-L) training data to hetero-chiral (D-L) design tasks. By implementing this method within a latent diffusion model, we achieved D-peptide binder design that not only outperforms existing tools in in silico benchmarks, but also demonstrates efficacy in wet-lab validation. To our knowledge, our approach represents the first experimentally validated AI generative model for the de novo design of D-peptide binders, offering new perspectives on handling chirality in protein design. Codes are available at https://github.com/YZY010418/PepMirror