SPPIDER-seq: Sequence-based partner-aware predictor of protein-protein interaction sites.
Alexey Porollo1, Om Jadhav2, Aaron Alvarez2
1Department of Biostatistics, Health Informatics and Data Sciences, the University of Cincinnati College of Medicine, Cincinnati, OH, USA 45267.
Biorxiv : the Preprint Server for Biology
|May 7, 2026
Summary
SPPIDER-seq is a new framework for predicting protein-protein interaction sites by considering partner context. It outperforms existing methods on disordered interfaces and reveals partner-specific binding patterns.
Area of Science:
- Computational Biology
- Structural Biology
- Bioinformatics
Background:
- Traditional protein-protein interaction (PPI) site predictors often ignore crucial partner-specific context.
- This limitation is particularly significant for transient and intrinsically disordered protein interactions.
Purpose of the Study:
- To introduce SPPIDER-seq, a novel partner-aware framework for predicting PPI sites.
- To develop models that account for interacting partner context in residue-level predictions.
Main Methods:
- Utilized pretrained ESM-2 embeddings and a cross-attention architecture for partner conditioning.
- Curated non-redundant protein-peptide interaction datasets from BioLiP for training.
- Developed and benchmarked two complementary models: receptor-centric and peptide-centric.
Main Results:
- SPPIDER-seq achieved high performance on blind benchmarks (AUROC up to 0.797, MCC up to 0.269).
- Outperformed AlphaFold3 on peptide-mediated and disordered interfaces, showing complementarity on globular complexes.
- Identified coherent, partner-specific interface patterns in TP53 interaction partners across different regions.
Conclusions:
- SPPIDER-seq effectively predicts PPI sites by incorporating partner-specific information.
- The framework advances the prediction of interactions involving disordered regions and protein-peptide binding.
- Demonstrated the utility of partner-aware context in understanding protein interaction specificity.
Related Concept Videos
02:04Protein-protein Interfaces
Many proteins form complexes to carry out their functions, making protein-protein interactions (PPIs) essential for an organism's survival. Most PPIs are stabilized by numerous weak noncovalent chemical forces. The physical shape of the interfaces determines the way two proteins interact. Many globular proteins have closely-matching shapes on their surfaces, which form a large number of weak bonds. Additionally, many PPIs occur between two helices or between a surface cleft and a polypeptide...
02:04Protein-Protein Interfaces
Many proteins form complexes to carry out their functions, making protein-protein interactions (PPIs) essential for an organism's survival. Most PPIs are stabilized by numerous weak noncovalent chemical forces. The physical shape of the interfaces determines the way two proteins interact. Many globular proteins have closely-matching shapes on their surfaces, which form a large number of weak bonds. Additionally, many PPIs occur between two helices or between a surface cleft and a polypeptide...
02:26Protein Networks
An organism can have thousands of different proteins, and these proteins must cooperate to ensure the health of an organism. Proteins bind to other proteins and form complexes to carry out their functions. Many proteins interact with multiple other proteins creating a complex network of protein interactions.
These interactions can be represented through maps depicting protein-protein interaction networks, represented as nodes and edges. Nodes are circles that are representative of a protein,...
These interactions can be represented through maps depicting protein-protein interaction networks, represented as nodes and edges. Nodes are circles that are representative of a protein,...
02:26Protein Networks
An organism can have thousands of different proteins, and these proteins must cooperate to ensure the health of an organism. Proteins bind to other proteins and form complexes to carry out their functions. Many proteins interact with multiple other proteins creating a complex network of protein interactions.
These interactions can be represented through maps depicting protein-protein interaction networks, represented as nodes and edges. Nodes are circles that are representative of a protein,...
These interactions can be represented through maps depicting protein-protein interaction networks, represented as nodes and edges. Nodes are circles that are representative of a protein,...
01:49Conserved Binding Sites
Many proteins’ biological role depends on their interactions with their ligands, small molecules that bind to specific locations on the protein known as ligand-binding sites. Ligand-binding sites are often conserved among homologous proteins as these sites are critical for protein function.
Binding sites are often located in large pockets, and if their location on a protein’s surface is unknown, it can be predicted using various approaches. The energetic method computationally analyses the...
Binding sites are often located in large pockets, and if their location on a protein’s surface is unknown, it can be predicted using various approaches. The energetic method computationally analyses the...
02:47Protein Families
Protein families are groups of homologous proteins; that is, they have similarities in amino acid sequences and three-dimensional structures. Protein families usually occur because of gene duplication, where an additional copy of a gene is inserted into the genome of an organism. Mutations that change the amino acids but still allow the protein to be properly synthesized, will lead to new protein family members. If these new proteins contain similar amino acids in key locations, protein...