Trainable subnetworks reveal insights into structure knowledge organization in protein language models

Protein language models (PLMs) pretrained via a masked language modeling objective have proven effective across a range of structure-related tasks, including high-resolution structure prediction. However, it remains unclear to what extent these models factorize protein structural categories among their learned parameters. In this work, we introduce trainable subnetworks, which mask out the PLM weights responsible for language modeling performance on a structural category of proteins. We systematically trained 39 PLM subnetworks targeting both sequence- and residue-level features at varying degrees of resolution using annotations defined by the CATH taxonomy and secondary structure elements. Using these PLM subnetworks, we assessed how structural factorization in PLMs influences downstream structure prediction. Our results show that PLMs are highly sensitive to sequence-level features and can predominantly disentangle extremely coarse or fine-grained information. Furthermore, we observe that structure prediction is highly responsive to factorized PLM representations and that small changes in language modeling performance can significantly impair PLM-based structure prediction capabilities. Our work presents a framework for studying feature entanglement within pretrained PLMs and can be leveraged to improve the alignment of learned PLM representations with known biological concepts.

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Publication Details

Journal
PLoS Computational Biology
Published
2026-02-09
DOI
https://doi.org/10.1371/journal.pcbi.1013925
Primary Topic
Machine Learning in Bioinformatics
Type
article
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article

Trainable subnetworks reveal insights into structure knowledge organization in protein language models

Ria Vinod, Ava P. Amini, Kevin Yang, Lorin Crawford
PLoS Computational Biology
Machine Learning in Bioinformatics
article

Trainable subnetworks reveal insights into structure knowledge organization in protein language models

Ria Vinod, Ava P. Amini, Kevin Yang, Lorin Crawford
article en

Abstract

Protein language models (PLMs) pretrained via a masked language modeling objective have proven effective across a range of structure-related tasks, including high-resolution structure prediction. However, it remains unclear to what extent these models factorize protein structural categories among their learned parameters. In this work, we introduce trainable subnetworks, which mask out the PLM weights responsible for language modeling performance on a structural category of proteins. We systematically trained 39 PLM subnetworks targeting both sequence- and residue-level features at varying degrees of resolution using annotations defined by the CATH taxonomy and secondary structure elements. Using these PLM subnetworks, we assessed how structural factorization in PLMs influences downstream structure prediction. Our results show that PLMs are highly sensitive to sequence-level features and can predominantly disentangle extremely coarse or fine-grained information. Furthermore, we observe that structure prediction is highly responsive to factorized PLM representations and that small changes in language modeling performance can significantly impair PLM-based structure prediction capabilities. Our work presents a framework for studying feature entanglement within pretrained PLMs and can be leveraged to improve the alignment of learned PLM representations with known biological concepts.

PLoS Computational BiologyVol. 22(2)
Microsoft (United States) (US), Brown University (US)
Quality Education
Openalex Percentile: Top 62%
Machine Learning in Bioinformatics
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Trainable subnetworks reveal insights into structure knowledge organization in protein language models — Ria Vinod, Ava P. Amini, et al. · PLoS Computational Biology (2026) | TGRS Research Map | TGRS