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PathFold: Predicting the Entire Protein Folding Pathway from Protein Sequence Alone

Zhang, Z.; Ibtehaz, N.; Kagaya, Y.; Xu, Z.; Punuru, P.; Kihara, D.

2026-09-01 bioinformatics
10.64898/2026.08.26.747321 bioRxiv
Show abstract

Recent advances in protein structure prediction, exemplified by AlphaFold, have largely addressed the determination of static structures, one aspect of the protein folding problem. However, predicting folding pathways, by which proteins reach their native states, remains a significant challenge. Here, we present PathFold, a deep learning framework that predicts protein folding pathways directly from sequence information. PathFold leverages an AlphaFold-based module to extract structural information from the sequence and generates a progressive folding trajectory from an extended conformation using a diffusion model. By modeling the full trajectory, it enables prediction of folding intermediates and transition pathways, analogous to those observed in steered molecular dynamics (SMD) simulations. The predicted pathways reveal well-defined intermediates and sequential folding events, and show agreement with experimental folding data, including measured {Phi}-values.

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