Structural Interpretations of Protein Language Model Representations via Differentiable Graph Partitioning

arXiv:2605.10985v1 Announce Type: new Abstract: Protein language models such as ESM-2 learn rich residue representations that achieve strong performance on protein function prediction, but their features remain difficult to interpret as structural & evolutionary signals are encoded in dense latent spaces. We propose a plug-&-play framework that projects ESM-2 representations onto protein contact graphs & applies extbf{SoftBlobGIN}, a lightweight Graph Isomorphism Network with differentiable Gumbel-softmax substructure pooling, to perform structure-aware message passing & learn coarse functional substructures for downstream prediction tasks. Across enzyme classification, SoftBlobGIN achieves 92.8% accuracy & 0.898 macro-F1. Unlike post hoc analysis of protein language models alone, our method produces directly auditable structural explanations: GNNExplainer recovers biologically meaningful active-site residues, spatially localized functional clusters, & catalytic contact patterns. On binding-site detection, SoftBlobGIN improves residue AUROC from 0.885 using an ESM-2 linear probe to 0.983, indicating that these structural explanations are not recoverable from language-model features alone. Learned blob partitions provide an additional layer of interpretability by automatically grouping residues into functional substructures, with blobs containing annotated active-site residues showing 1.85imes higher importance than other blobs (rho{=}0.339, p{=}0.009), without any active-site supervision. Our framework requires no retraining of the language model, adds only sim1.1M parameters, & generalises across ProteinShake tasks, achieving F_{max} of 0.733 on Gene Ontology prediction & AUROC of 0.969 on binding-site detection. We position this as an interpretable structural companion to protein language models that makes their predictions more transparent & auditable.

Source: arXiv cs.LG | 2026-05-13