PPDiff: Diffusing in Hybrid Sequence-Structure Space for Protein-Protein Complex Design

Zhenqiao Song, Tianxiao Li, Lei Li, Martin Renqiang Min
Proceedings of the 42nd International Conference on Machine Learning, PMLR 267:56319-56336, 2025.

Abstract

Designing protein-binding proteins with high affinity is critical in biomedical research and biotechnology. Despite recent advancements targeting specific proteins, the ability to create high-affinity binders for arbitrary protein targets on demand, without extensive rounds of wet-lab testing, remains a significant challenge. Here, we introduce PPDiff, a diffusion model to jointly design the sequence and structure of binders for arbitrary protein targets in a non-autoregressive manner. PPDiff builds upon our developed Sequence Structure Interleaving Network with Causal attention layers (SSINC), which integrates interleaved self-attention layers to capture global amino acid correlations, $k$-nearest neighbor ($k$NN) equivariant graph convolutional layers to model local interactions in three-dimensional (3D) space, and causal attention layers to simplify the intricate interdependencies within the protein sequence. To assess PPDiff, we curate PPBench, a general protein-protein complex dataset comprising 706,360 complexes from the Protein Data Bank (PDB). The model is pretrained on PPBench and finetuned on two real-world applications: target-protein mini-binder complex design and antigen-antibody complex design. PPDiff consistently surpasses baseline methods, achieving success rates of 50.00%, 23.16%, and 16.89% for the pretraining task and the two downstream applications, respectively.

Cite this Paper

BibTeX
@InProceedings{pmlr-v267-song25d, title = {{PPD}iff: Diffusing in Hybrid Sequence-Structure Space for Protein-Protein Complex Design}, author = {Song, Zhenqiao and Li, Tianxiao and Li, Lei and Min, Martin Renqiang}, booktitle = {Proceedings of the 42nd International Conference on Machine Learning}, pages = {56319--56336}, year = {2025}, editor = {Singh, Aarti and Fazel, Maryam and Hsu, Daniel and Lacoste-Julien, Simon and Berkenkamp, Felix and Maharaj, Tegan and Wagstaff, Kiri and Zhu, Jerry}, volume = {267}, series = {Proceedings of Machine Learning Research}, month = {13--19 Jul}, publisher = {PMLR}, pdf = {https://raw.githubusercontent.com/mlresearch/v267/main/assets/song25d/song25d.pdf}, url = {https://proceedings.mlr.press/v267/song25d.html}, abstract = {Designing protein-binding proteins with high affinity is critical in biomedical research and biotechnology. Despite recent advancements targeting specific proteins, the ability to create high-affinity binders for arbitrary protein targets on demand, without extensive rounds of wet-lab testing, remains a significant challenge. Here, we introduce PPDiff, a diffusion model to jointly design the sequence and structure of binders for arbitrary protein targets in a non-autoregressive manner. PPDiff builds upon our developed Sequence Structure Interleaving Network with Causal attention layers (SSINC), which integrates interleaved self-attention layers to capture global amino acid correlations, $k$-nearest neighbor ($k$NN) equivariant graph convolutional layers to model local interactions in three-dimensional (3D) space, and causal attention layers to simplify the intricate interdependencies within the protein sequence. To assess PPDiff, we curate PPBench, a general protein-protein complex dataset comprising 706,360 complexes from the Protein Data Bank (PDB). The model is pretrained on PPBench and finetuned on two real-world applications: target-protein mini-binder complex design and antigen-antibody complex design. PPDiff consistently surpasses baseline methods, achieving success rates of 50.00%, 23.16%, and 16.89% for the pretraining task and the two downstream applications, respectively.} }
Endnote
%0 Conference Paper %T PPDiff: Diffusing in Hybrid Sequence-Structure Space for Protein-Protein Complex Design %A Zhenqiao Song %A Tianxiao Li %A Lei Li %A Martin Renqiang Min %B Proceedings of the 42nd International Conference on Machine Learning %C Proceedings of Machine Learning Research %D 2025 %E Aarti Singh %E Maryam Fazel %E Daniel Hsu %E Simon Lacoste-Julien %E Felix Berkenkamp %E Tegan Maharaj %E Kiri Wagstaff %E Jerry Zhu %F pmlr-v267-song25d %I PMLR %P 56319--56336 %U https://proceedings.mlr.press/v267/song25d.html %V 267 %X Designing protein-binding proteins with high affinity is critical in biomedical research and biotechnology. Despite recent advancements targeting specific proteins, the ability to create high-affinity binders for arbitrary protein targets on demand, without extensive rounds of wet-lab testing, remains a significant challenge. Here, we introduce PPDiff, a diffusion model to jointly design the sequence and structure of binders for arbitrary protein targets in a non-autoregressive manner. PPDiff builds upon our developed Sequence Structure Interleaving Network with Causal attention layers (SSINC), which integrates interleaved self-attention layers to capture global amino acid correlations, $k$-nearest neighbor ($k$NN) equivariant graph convolutional layers to model local interactions in three-dimensional (3D) space, and causal attention layers to simplify the intricate interdependencies within the protein sequence. To assess PPDiff, we curate PPBench, a general protein-protein complex dataset comprising 706,360 complexes from the Protein Data Bank (PDB). The model is pretrained on PPBench and finetuned on two real-world applications: target-protein mini-binder complex design and antigen-antibody complex design. PPDiff consistently surpasses baseline methods, achieving success rates of 50.00%, 23.16%, and 16.89% for the pretraining task and the two downstream applications, respectively.
APA
Song, Z., Li, T., Li, L. & Min, M.R.. (2025). PPDiff: Diffusing in Hybrid Sequence-Structure Space for Protein-Protein Complex Design. Proceedings of the 42nd International Conference on Machine Learning, in Proceedings of Machine Learning Research 267:56319-56336 Available from https://proceedings.mlr.press/v267/song25d.html.

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