biostudies-literaturePeng FZU.S. Department of Health & Human Services | NIH | National Institute of General Medical SciencesU.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)945-949https://www.ebi.ac.uk/biostudies/studies/S-EPMC12074982biostudies-literatureUnknown22(5)Current protein language models (LMs) accurately encode protein properties but have yet to represent post-translational modifications (PTMs), which are crucial for proteomic diversity and influence protein structure, function and interactions. To address this gap, we develop PTM-Mamba, a PTM-aware protein LM that integrates PTM tokens using bidirectional Mamba blocks fused with ESM-2 protein LM embeddings via a newly developed gating mechanism. PTM-Mamba uniquely models both wild-type and PTM sequences, enabling downstream tasks such as disease association and druggability prediction, PTM effect prediction on protein-protein interactions and zero-shot PTM discovery. In total, our work establishes PTM-Mamba as a foundational tool for PTM-aware protein modeling and design.Nature methodsPTM-Mamba: a PTM-aware protein language model with bidirectional gated Mamba blocks.PMC120749821R35GM1555282-01Schussheim BWang CChatterjee PVincoff SPeng FZChen TfalsePTM-Mamba: a PTM-aware protein language model with bidirectional gated Mamba blocks.Current protein language models (LMs) accurately encode protein properties but have yet to represent post-translational modifications (PTMs), which are crucial for proteomic diversity and influence protein structure, function and interactions. To address this gap, we develop PTM-Mamba, a PTM-aware protein LM that integrates PTM tokens using bidirectional Mamba blocks fused with ESM-2 protein LM embeddings via a newly developed gating mechanism. PTM-Mamba uniquely models both wild-type and PTM sequences, enabling downstream tasks such as disease association and druggability prediction, PTM effect prediction on protein-protein interactions and zero-shot PTM discovery. In total, our work establishes PTM-Mamba as a foundational tool for PTM-aware protein modeling and design.2025-01-01T00:00:00Z2025 May2026-06-02T07:06:43.332Z2026-04-15T03:15:26.839ZS-EPMC120749824021100410.1038/s41592-025-02656-9