De novo protein design in an expanded chemical space
- 1Peking University
Abstract
Generative protein design has made sequence and structure programmable, yet its chemical alphabet remains largely confined to the canonical twenty. Here, we establish CheMoDesign, an experimentally validated generative framework for designing proteins de novo around user-specified chemistry. CheMoDesign weakens pair-representation conditioning in a pretrained all-atom structure-prediction model while preserving chemical anchors, then refines generated backbones through sequence-conditioned denoising. By treating post-translational modifications, synthetic residues, and chemical modifications as user-defined building blocks, the framework generated proteins with chemistry-dependent recognition and reactivity in single-round experimental campaigns. Sulfotyrosine and nitrotyrosine enabled modification-dependent recognition of thrombin and HER2, respectively. Genetically encoded noncanonical residues enabled bioorthogonal affinity switching and light- or proximity-triggered covalent target capture. Post-expression chemical modifications yielded a light-activated covalent PD-L1 binder and an isoform-selective CA IX inhibitor (KD = 45 nM) designed to engage catalytic Zn2+;. CheMoDesign makes chemical mechanism a programmable dimension of de novo protein design.
Related
- Bridging MS2 Spectra and Chemical Space: Advances in Spectral Similarity, Molecular Retrieval, and De Novo Structure Discovery
- De novo Rubisco design with protein language models
- Aptamers without SELEX: De novo design from protein structure in hours
- EquiDesign: a versatile computational framework for de novo protein sequence design.
- RiboBridge: protein-conditioned de novo RNA binder structure design
BibTeX
@misc{li2026novo,
title = {{De novo protein design in an expanded chemical space}},
author = {Y. Li and Y. Jing and Y. Su and W. Ren and J. Zhang and T. Liu},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.08.757794},
url = {https://www.biorxiv.org/content/10.64898/2026.10.08.757794v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - De novo protein design in an expanded chemical space
AU - Y. Li
AU - Y. Jing
AU - Y. Su
AU - W. Ren
AU - J. Zhang
AU - T. Liu
PY - 2026
DA - 2026/10/08
PB - bioRxiv
DO - 10.64898/2026.10.08.757794
UR - https://www.biorxiv.org/content/10.64898/2026.10.08.757794v1
AB - Generative protein design has made sequence and structure programmable, yet its chemical alphabet remains largely confined to the canonical twenty. Here, we establish CheMoDesign, an experimentally validated generative framework for designing proteins de novo around user-specified chemistry. CheMoDesign weakens pair-representation conditioning in a pretrained all-atom structure-prediction model while preserving chemical anchors, then refines generated backbones through sequence-conditioned denoising. By treating post-translational modifications, synthetic residues, and chemical modifications as user-defined building blocks, the framework generated proteins with chemistry-dependent recognition and reactivity in single-round experimental campaigns. Sulfotyrosine and nitrotyrosine enabled modification-dependent recognition of thrombin and HER2, respectively. Genetically encoded noncanonical residues enabled bioorthogonal affinity switching and light- or proximity-triggered covalent target capture. Post-expression chemical modifications yielded a light-activated covalent PD-L1 binder and an isoform-selective CA IX inhibitor (KD = 45 nM) designed to engage catalytic Zn2+;. CheMoDesign makes chemical mechanism a programmable dimension of de novo protein design.
ER -