Explainable protein-protein binding affinity prediction via fine-tuning protein language models

Abstract

Protein-protein interactions underpin virtually every aspect of cellular life, and the precise quantification of their binding affinity is fundamental to understanding immune recognition, disease mechanisms, and the rational design of therapeutic antibodies. Yet predicting binding affinity at scale remains an unsolved challenge: reliable experimental assays are low-throughput and expensive, while computational methods that depend on three-dimensional complex struc-tures cannot be applied to the vast majority of clinically relevant targets where structural data are absent. Here we present BALM-PPI, a framework that predicts protein-protein binding affinity from amino acid sequence alone. Both proteins are encoded by a protein language model trained on evolutionary sequence data and projected into a shared representational space, where their distance directly reflects binding strength. Fine-tuning this protein language model requires updating fewer than 1% of its parameters, and we show that this targeted adaptation steers the model toward interface-relevant sequence signals rather than spurious background correlations. On a curated benchmark of over 12,000 protein complexes, BALM-PPI matches or exceeds the accuracy of structure-based methods and retains predictive power for proteins with less than 30% sequence identity to the training set. Using only a subset of project-specific assay data, BALM-PPI outperforms a recent method trained on three times the data, suggesting that the model has already encoded the underlying interaction signals and requires only minimal supervision to specialise to a new target. BALM-PPI further provides residue-level attribution maps that pinpoint the amino acid positions driving each affinity prediction, consistently re-covering experimentally validated interaction hotspots across enzyme-inhibitor, signalling, and antibody-antigen systems without any structural input during training. This allows predictions to be cross-validated against structural and mutagenesis evidence, providing a mechanistic basis for candidate shortlisting ahead of experimental follow-up. BALM-PPI is freely accessible via an interactive web server.