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Embedding-based alignment: combining protein language models with dynamic programming alignment to detect structural

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Protein language models (pLMs) offer new bioinformatics tools. Our embedding-based protein sequence alignment (EBA) method effectively identifies distant protein relationships, outperforming existing approaches.

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Area of Science:

  • Bioinformatics
  • Computational Biology
  • Structural Biology

Background:

  • Protein language models (pLMs) are advanced AI tools increasingly applied to biological sequences.
  • pLMs generate residue-level embeddings that capture the functional context of amino acids within a protein.
  • These embeddings have shown promise in downstream tasks, including identifying homologous proteins.

Purpose of the Study:

  • To introduce a novel method for generating protein sequence alignments using embeddings from pLMs.
  • To evaluate the performance of this new method in detecting structural similarities, especially in the challenging 'twilight zone' of homology.
  • To demonstrate the utility of combining pLMs with alignment techniques for protein relationship discovery.

Main Methods:

  • Development of an embedding-based protein sequence alignment (EBA) method.
  • Utilizing per-residue embeddings generated by protein language models.
  • Benchmarking EBA against classical alignment methods and other pLM-based approaches.

Main Results:

  • EBA successfully captures structural similarities between proteins, even in the twilight zone.
  • The method achieves high accuracy without requiring training or parameter optimization.
  • EBA outperforms both traditional sequence alignment and other pLM-based methods in detecting distant relationships.

Conclusions:

  • The integration of protein language models with alignment strategies is a powerful approach for bioinformatics.
  • EBA provides a robust and accurate tool for identifying homologous proteins, particularly those with low sequence identity.
  • This method advances the detection of evolutionary and structural relationships in protein sequences.