arXiv Machine Learning By Paulo Yanez Sarmiento, Pia Francesca Rissom, Manuel Pfeuffer, Marco Simnacher, Jordan F. Safer, Sumaiya Iqbal, Henrike O. Heyne, Nadja Klein, Bernhard Y. Renard

Interpreting Protein Language Model Embeddings via Orthogonal Projection for Protein Fitness Prediction

Read the original on arXiv Machine Learning →

The paper introduces a method that uses orthogonal projection to remove the influence of known biochemical features from protein language model (PLM) embeddings, allowing the authors to assess how much these features contribute to protein fitness predictions. By applying this technique to high‑order and interaction effects, they demonstrate that eliminating these interpretable features reduces downstream classifier performance, indicating that PLM embeddings encode patterns correlated with biochemical properties. The authors also show that these biochemical features explain a substantial portion of the variance in the classifier’s predictions, suggesting that PLM embeddings capture biologically relevant information.

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arXiv Machine Learning
Aug 28

Interpreting Latent Protein Language Model Features with Geometric Annotations

The paper introduces a scalable method to interpret sparse autoencoder (SAE) features in the ESM-2 protein language model by leveraging geometrically inspired features of the protein α‑carbon backbone. Across 8M layers of ESM-2, a false discovery rate–controlled analysis shows that local geometry is significantly associated with many SAE features, revealing substructure within known biological labels and enabling annotation of unannotated metagenomic proteins. Ablation experiments demonstrate that removing these geometric features shifts ESM-2’s predicted contact maps toward the descriptor, linking mechanistic interpretability with structural biology.

By Siddharth Setlur, Djordje Mihajlovic, Darrick Lee