Porollo, A.; Jadhav, O.; Alvarez, A.; Chen, J.

Motivation: Sequence-based protein-protein interaction (PPI) site predictors typically analyze proteins in isolation, neglecting partner-specific context that is critical for interface specificity, particularly in transient and disordered interactions. Results: We introduce SPPIDER-seq, a partner-aware PPI site prediction framework that combines pretrained ESM-2 embeddings with a cross-attention architecture to enable residue-level conditioning on interacting partners. We curated non-redundant protein-peptide interaction datasets from BioLiP and used them to train and benchmark two complementary models: a receptor-centric model optimized for structured interfaces and a peptide-centric model tailored to disordered, motif-driven binding. On blind benchmarks, SPPIDER-seq achieved AUROC values up to 0.797 and MCC values up to 0.269, outperforming AlphaFold3 on peptide-mediated and disordered interfaces while remaining complementary on globular complexes. Application to 341 TP53 interaction partners revealed coherent, partner-specific interface patterns across both structured and intrinsically disordered regions. Availability and Implementation: SPPIDER-seq models, datasets, and the Python code are freely available on the web at: https://github.com/aporollo-lab/SPPIDER-seq