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A Protocol for Computer-Based Protein Structure and Function Prediction
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Balancing Gene Ontology annotation specificity in protein function prediction based on the protein sequence large

Jiangyi Shao1,2, Shutao Chen1, Ziwen Wang1

  • 1School of Computer Science and Technology, Beijing Institute of Technology, Beijing 100081, China.

Genome Research
|April 15, 2026
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We developed ProGO-PSL, a novel graph architecture to address the imbalance between low- and high-specificity Gene Ontology (GO) terms for accurate protein function prediction. This method enhances drug discovery and understanding of biological systems.

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Area of Science:

  • Bioinformatics
  • Computational Biology
  • Genomics

Background:

  • Accurate protein function prediction is crucial for drug discovery and precision medicine.
  • Gene Ontology (GO) provides a standardized framework, but an imbalance between low- and high-specificity terms hinders comprehensive analysis.
  • This imbalance creates blind spots in understanding protein function, especially in clinically relevant pathways.

Purpose of the Study:

  • To present ProGO-PSL, a novel large graph architecture designed to resolve the imbalance between low- and high-specificity GO terms.
  • To improve the accuracy and completeness of protein function prediction.
  • To enable a more thorough functional characterization of the proteome.

Main Methods:

  • ProGO-PSL leverages explicit domain identifiers from InterPro and evolutionary context from Multiple Sequence Alignments.
  • A powerful imbalance learning framework is employed to fuse these complementary data sources.
  • The model utilizes a large graph architecture for integrated data analysis.

Main Results:

  • ProGO-PSL consistently outperforms state-of-the-art methods by 5-15% across all specificity levels.
  • The model demonstrates robust generalization on both benchmark and independent test datasets.
  • Interpretable representations are generated, clarifying relationships between GO terms of varying specificity.

Conclusions:

  • ProGO-PSL effectively addresses the challenge of GO term imbalance in protein function prediction.
  • The approach enables more complete functional characterization of proteins and the proteome.
  • This work accelerates the identification of therapeutic targets in uncharacterized biological pathways.