AlphaFold 2, but not AlphaFold 3, predicts confident but unrealistic β-solenoid structures for repeat proteins.


Pratt, Olivia S, Elliott, Luc G, Haon, Margaux ORCID: 0009-0005-1192-6399, Mesdaghi, Shahram, Price, Rebecca M ORCID: 0009-0003-1777-0925, Simpkin, Adam J ORCID: 0000-0003-1883-9376 and Rigden, Daniel J ORCID: 0000-0002-7565-8937 (2025) AlphaFold 2, but not AlphaFold 3, predicts confident but unrealistic β-solenoid structures for repeat proteins. Computational and structural biotechnology journal, 27. pp. 467-477. ISSN 2001-0370, 2001-0370

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Abstract

AlphaFold 2 (AF2) has revolutionised protein structure prediction but, like any new tool, its performance on specific classes of targets, especially those potentially under-represented in its training data, merits attention. Prompted by a highly confident prediction for a biologically meaningless, randomly permuted repeat sequence, we assessed AF2 performance on sequences composed of perfect repeats of random sequences of different lengths. AF2 frequently folds such sequences into β-solenoids which, while ascribed high confidence, contain unusual and implausible features such as internally stacked and uncompensated charged residues. A number of sequences confidently predicted as β-solenoids are predicted by other advanced methods as intrinsically disordered. The instability of some predictions is demonstrated by molecular dynamics. Importantly, other deep learning-based structure prediction tools predict different structures or β-solenoids with much lower confidence suggesting that AF2 alone has an unreasonable tendency to predict confident but unrealistic β-solenoids for perfect repeat sequences. The potential implications for structure prediction of natural (near-)perfect sequence repeat proteins are also explored.

Item Type: Article
Uncontrolled Keywords: Alphafold, Beta-solenoid, Model confidence, Repeat proteins, Structure prediction
Divisions: Faculty of Health and Life Sciences
Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology
Depositing User: Symplectic Admin
Date Deposited: 14 Feb 2025 10:20
Last Modified: 14 Feb 2025 10:20
DOI: 10.1016/j.csbj.2025.01.016
Open Access URL: https://doi.org/10.1016/j.csbj.2025.01.016
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URI: https://livrepository.liverpool.ac.uk/id/eprint/3190290
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