OTalign: Optimal Transport Alignment for Remote Protein Homologs Using Protein Language Model Embeddings

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ID: 319318
2026
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Abstract
MOTIVATION: Protein sequence alignment is a crucial task in bioinformatics, yet aligning remote homologs with low sequence identity remains a longstanding challenge, particularly due to the difficulty of handling gaps. We introduce a new method that applies Optimal Transport (OT) theory to sequence alignment, providing a mathematically principled framework for modeling residue matches and gaps. RESULTS: OTalign formulates sequence alignment as an entropy-regularized unbalanced optimal transport (UOT) problem over embeddings derived from protein language models (PLMs). Unlike traditional methods, it introduces position-specific gap penalties that adapt to each sequence pair. On challenging remote-homolog benchmarks (SABmark, MALIDUP, MALISAM), OTalign consistently outperforms baselines (Needleman-Wunsch, HHalign) and recent PLM-based methods (PLMAlign, DeepBLAST), achieving F1 scores of 0.594 on SABmark Superfamily and 0.358 on SABmark Twilight. Furthermore, OTalign provides a quantitative and interpretable metric of how effectively PLM embeddings represent sequence similarity relationships. Finally, its differentiable nature enables end-to-end fine-tuning of PLMs, establishing a framework for learning embeddings explicitly optimized for alignment tasks. AVAILABILITY AND IMPLEMENTATION: This code is available at https://github.com/DeepFoldProtein/OTalign. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
Reference Key
openalex_W7166880154 Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Minsoo Kim, Hanjin Bae, Gyeongpil Jo, Kunwoo Kim, Jejoong Yoo, Keehyoung Joo
Journal BMC Bioinformatics
Year 2026
DOI
10.1093/bioinformatics/btag476
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