Deep-learning-based single-domain and multidomain protein structure prediction with D-I-TASSER

W Zheng and Q Wuyun and Y Li and QC Liu and XG Zhou and CX Peng and YH Zhu and L Freddolino and Y Zhang, NATURE BIOTECHNOLOGY (2025).

DOI: 10.1038/s41587-025-02654-4

The dominant success of deep learning techniques on protein structure prediction has challenged the necessity and usefulness of traditional force field-based folding simulations. We proposed a hybrid approach, deep-learning-based iterative threading assembly refinement (D-I- TASSER), which constructs atomic-level protein structural models by integrating multisource deep learning potentials with iterative threading fragment assembly simulations. D-I-TASSER introduces a domain splitting and assembly protocol for the automated modeling of large multidomain protein structures. Benchmark tests and the most recent critical assessment of protein structure prediction, 15 experiments demonstrate that D-I-TASSER outperforms AlphaFold2 and AlphaFold3 on both single-domain and multidomain proteins. Large-scale folding experiments further show that D-I-TASSER could fold 81% of protein domains and 73% of full-chain sequences in the human proteome with results highly complementary to recently released models by AlphaFold2. These results highlight a new avenue to integrate deep learning with classical physics-based folding simulations for high-accuracy protein structure and function predictions that are usable in genome-wide applications.

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