ThermoFusion: A Multimodal Deep Learning Framework for Generalizable Prediction of Enzyme Thermostability
Abstract
Protein thermostability is a critical property for both industrial and biomedical enzyme applications, yet experimental evaluation of mutation-induced stability changes remains laborious and costly. Here, we present ThermoFusion, a hybrid deep learning framework that integrates 3D protein structure embeddings from ThermoMPNN with sequence-based embeddings from the pretrained protein language model ESM2 to predict the effects of single-point mutations on protein stability ({Delta}{Delta}G). ThermoFusion exhibits robust generalization, maintaining high predictive accuracy across out of distribution sequences with low identity to the training set -- a scenario where many other machine learning models, including ThermoMPNN and state-of-the-art tools, perform poorly due to reliance on memorization. Benchmarking on a curated enzyme dataset comprising of 105 enzymes and 3144 mutations shows that ThermoFusion reliably identifies stabilizing mutations while accurately predicting stability for enzymes beyond its training set. These results establish ThermoFusion as a powerful tool for rational enzyme design beyond its training set.
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- biorxiv v1 2026-07-07 source ↗
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AI x Bio Discovery @aixbiobot.bsky.social · 787 followers neutral
ThermoFusion: A Multimodal Deep Learning Framework for Generalizable Prediction of Enzyme Thermostability [new] ...integrates 3D struct/seq embeds to predict single-point mut. effects on stability, enabling robust gen. to novel enz.
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bioRxiv Bioinfo @biorxiv-bioinfo.bsky.social · 4920 followers neutral
ThermoFusion: A Multimodal Deep Learning Framework for Generalizable Prediction of Enzyme Thermostability https://www.biorxiv.org/content/10.64898/2026.07.04.736494v1
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bioRxivpreprint @biorxivpreprint.bsky.social · 8895 followers neutral
ThermoFusion: A Multimodal Deep Learning Framework for Generalizable Prediction of Enzyme Thermostability https://www.biorxiv.org/content/10.64898/2026.07.04.736494v1