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

arXiv:2602.20176v2 Announce Type: replace-cross Abstract: 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 extit{in silico} benchmarks, but also demonstrates efficacy in wet-lab validation. To our knowledge, our approach represents the first wet-lab validated generative AI for the extit{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 .

Source: arXiv cs.LG | 2026-05-29