Cross-Chirality Generalization by Axial Vectors for Hetero-Chiral Protein-Peptide Interaction Design
Ziyi Yang, Zitong Tian, Yinjun Jia, Tianyi Zhang, Jiqing Zheng, Hao Wang, Yubu Su, Juncai He
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 *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.
BibTeX
@inproceedings{
yang2026crosschirality,
title={Cross-Chirality Generalization by Axial Vectors for Hetero-Chiral Protein-Peptide Interaction Design},
author={Ziyi Yang and Zitong Tian and Yinjun Jia and Tianyi Zhang and Jiqing Zheng and Hao Wang and Yubu Su and Juncai He and Lei Liu and Yanyan Lan},
booktitle={Forty-third International Conference on Machine Learning},
year={2026},
url={https://openreview.net/forum?id=mAusAlRZ0a}
}