PLM-eXplain: Divide and Conquer the Protein Embedding Space

Protein language models (PLMs) have revolutionised computational biology through their ability to generate powerful sequence representations for diverse prediction tasks. However, their black-box nature limits biological interpretation and translation to actionable insights. We present an explainable adapter layer - PLM-eXplain (PLM-X), that bridges this gap by factoring PLM embeddings into two components: an interpretable subspace based on established biochemical features, and a residual subspace that preserves the model's predictive power. Using embeddings from ESM2, our adapter incorporates well-established properties, including secondary structure and hydropathy while maintaining high performance. We demonstrate the effectiveness of our approach across three protein-level classification tasks: prediction of extracellular vesicle association, identification of transmembrane helices, and prediction of aggregation propensity. PLM-X enables biological interpretation of model decisions without sacrificing accuracy, offering a generalisable solution for enhancing PLM interpretability across various downstream applications. This work addresses a critical need in computational biology by providing a bridge between powerful deep learning models and actionable biological insights.

PatchProt: Hydrophobic patch prediction using protein foundation models

Hydrophobic patches on protein surfaces play important functional roles in protein-protein and protein-ligand interactions. Large hydrophobic surfaces are also involved in the progression of aggregation diseases. Predicting exposed hydrophobic patches from a protein sequence has been shown to be a difficult task. Fine-tuning foundation models allows for adapting a model to the specific nuances of a new task using a much smaller dataset. Additionally, multi-task deep learning offers a promising solution for addressing data gaps, simultaneously outperforming single-task methods. In this study, we harnessed a recently released leading large language model ESM-2. Efficient fine-tuning of ESM-2 was achieved by leveraging a recently developed parameter-efficient fine-tuning method. This approach enabled comprehensive training of model layers without excessive parameters and without the need to include a computationally expensive multiple sequence analysis. We explored several related tasks, at local (residue) and global (protein) levels, to improve the representation of the model. As a result, our fine-tuned ESM-2 model, PatchProt, cannot only predict hydrophobic patch areas but also outperforms existing methods at predicting primary tasks, including secondary structure and surface accessibility predictions. Importantly, our analysis shows that including related local tasks can improve predictions on more difficult global tasks. This research sets a new standard for sequence-based protein property prediction and highlights the remarkable potential of fine-tuning foundation models enriching the model representation by training over related tasks.