ProtLink: Sequence and Multispecies Graph Context for Protein Interaction Prediction

Abstract

Predicting protein-protein interactions (PPIs) from sequence alone is difficult, while known interaction networks may provide informative biological context. We introduce ProtLink, a sequence-conditioned graph-learning framework that combines frozen ESM-2 representations with protein interaction topology and orthogroup-mediated connections between species. We compare sequence-only models, GraphSAGE, a homogeneous graph transformer, and a heterogeneous graph transformer (HGT) for human PPI prediction. In an initial edge-level comparison, three-layer multispecies HGT with ESM-2 650M features achieves an average precision (AP) of 0.980 under random negative sampling, compared with 0.951 for the homogeneous transformer; its AP decreases to 0.878 with two-hop-preferred negatives. In controlled three-seed experiments, three-layer full-graph HGT obtains an AP of $0.9701\pm 0.0022$, exceeding an orthogroup-only model ($0.9435\pm 0.0094$). The corresponding two-layer comparison shows little additional benefit from non-human PPI edges, consistent with the greater message-passing depth needed to transmit their information. For human proteins excluded from training interactions, multispecies HGT achieves $0.8335\pm 0.0094$ AP versus $0.6482\pm 0.0052$ for a sequence-only pair model. These results identify the value, depth dependence, and limits of evolutionary graph context while distinguishing prediction of held-out edges from generalization to held-out proteins.

arXiv commentSubmitted to AI for Scientific Research at AAAI 2027