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A Protocol for Computer-Based Protein Structure and Function Prediction

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Published on: November 3, 2011

Modeling intrinsically disordered regions from AlphaFold2 to AlphaFold3.

Mahta Mehdiabadi¹, Silvio C E Tosatto^1,2, Damiano Piovesan¹

¹Department of Biomedical Sciences, University of Padova, Padua, Italy.

Protein Science : a Publication of the Protein Society

|December 27, 2025

Summary

This summary is machine-generated.

AlphaFold3 does not outperform AlphaFold2 in predicting intrinsically disordered regions (IDRs). AlphaFold2 is preferred for IDR identification due to comparable predictions and avoidance of structural hallucinations.

Keywords:

AlphaFold critical assessment of protein intrinsic disorder hallucinations intrisic protein disorder structure prediction

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Area of Science:

Structural bioinformatics
Computational biology
Protein structure prediction

Background:

AlphaFold2 excels at predicting globular protein structures but represents intrinsically disordered regions (IDRs) as static loops.
AlphaFold3 incorporates architectural changes to improve disordered region prediction and reduce structural hallucinations.

Purpose of the Study:

To compare the performance of AlphaFold3 and AlphaFold2 in predicting intrinsically disordered regions (IDRs).
To evaluate the effectiveness of new architectural modifications in AlphaFold3 for disorder prediction.

Main Methods:

Performance evaluation using the CAID3 benchmark dataset.
Comparative analysis of AlphaFold2 and AlphaFold3 predictions for IDRs.
Assessment of solvent accessibility, secondary structure content, and pLDDT scores as predictors of disorder.

Main Results:

AlphaFold3 did not outperform AlphaFold2 on the CAID3 benchmark for IDR prediction.
Solvent accessibility proved a consistent predictor of intrinsic disorder for both models.
Differences in predicted secondary structure and pLDDT scores influenced disorder interpretation between models.

Conclusions:

AlphaFold2 remains a reliable choice for identifying intrinsically disordered regions.
AlphaFold2 provides comparable IDR predictions to AlphaFold3 without introducing structural hallucinations.
Further investigation into secondary structure and pLDDT interpretation is warranted for advanced disorder prediction.