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

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 predict

SUBMITTER: Pratt OS 

PROVIDER: S-EPMC11795689 | biostudies-literature | 2025

REPOSITORIES: biostudies-literature