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

Designing protein-binding proteins with high affinity is critical in biomedical research and biotechnology. Despite recent advancements targeting specific proteins, the ability to create highaffinity 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 (kNN) equivariant graph 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 proteinprotein 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 minibinder 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. The code, data and models are available at https://github.com/JocelynSong/ PPDiff .