OpenFold: retraining AlphaFold2 yields new insights into its learning mechanisms and capacity for generalization

Machine Learning


  • Anfinsen, C. B. Principles that govern the folding of protein chains. Science 181, 223–230 (1973).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Dill, K. A., Ozkan, S. B., Shell, M. S. & Weikl, T. R. The protein folding problem. Annu. Rev. Biophys. 37, 289–316 (2008).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Jones, D. T., Singh, T., Kosciolek, T. & Tetchner, S. MetaPSICOV: combining coevolution methods for accurate prediction of contacts and long range hydrogen bonding in proteins. Bioinformatics 31, 999–1006 (2015).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Golkov, V. et al. Protein contact prediction from amino acid co-evolution using convolutional networks for graph-valued images. In Advances in Neural Information Processing Systems (eds Lee, D. et al.) (Curran Associates, 2016).

  • Wang, S., Sun, S., Li, Z., Zhang, R. & Xu, J. Accurate de novo prediction of protein contact map by ultra-deep learning model. PLoS Comput. Biol. 13, e1005324 (2017).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Liu, Y., Palmedo, P., Ye, Q., Berger, B. & Peng, J. Enhancing evolutionary couplings with deep convolutional neural networks. Cell Syst. 6, 65–74 (2018).

    Article 
    PubMed 

    Google Scholar 

  • Senior, A. W. et al. Improved protein structure prediction using potentials from deep learning. Nature 577, 706–710 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Xu, J., McPartlon, M. & Li, J. Improved protein structure prediction by deep learning irrespective of co-evolution information. Nat. Mach. Intell. 3, 601–609 (2021).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Šali, A. & Blundell, T. L. Comparative protein modelling by satisfaction of spatial restraints. J. Mol. Biol. 234, 779–815 (1993).

    Article 
    PubMed 

    Google Scholar 

  • Roy, A., Kucukural, A. & Zhang, Y. I-TASSER: a unified platform for automated protein structure and function prediction. Nat. Protoc. 5, 725–738 (2010).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Jumper, J. et al. Highly accurate protein structure prediction with AlphaFold. Nature 577, 583–589 (2021).

    Article 

    Google Scholar 

  • Mirdita, M. et al. ColabFold: making protein folding accessible to all. Nat. Methods 19, 679–682 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Baek, M. Adding a big enough number for ‘residue_index’ feature is enough to model hetero-complex using AlphaFold (green&cyan: crystal structure / magenta: predicted model w/ residue_index modification). Twitter twitter.com/minkbaek/status/1417538291709071362?lang=en (2021).

  • Tsaban, T. et al. Harnessing protein folding neural networks for peptide–protein docking. Nat. Commun. 13, 176 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Roney, J. P. & Ovchinnikov, S. State-of-the-art estimation of protein model accuracy using AlphaFold. Phys. Rev. Lett. 129, 238101 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Baltzis, A. et al. Highly significant improvement of protein sequence alignments with AlphaFold2. Bioinformatics 38, 5007–5011 (2022).

  • Bryant, P., Pozzati, G. & Elofsson, A. Improved prediction of protein–protein interactions using AlphaFold2. Nat. Commun. 13, 1265 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Wayment-Steele, H. K., Ovchinnikov, S., Colwell, L. & Kern, D. Prediction of multiple conformational states by combining sequence clustering with AlphaFold2. Nature 625, 832–839 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Tunyasuvunakool, K. et al. Highly accurate protein structure prediction for the human proteome. Nature 596, 590–596 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Varadi, M. et al. AlphaFold Protein Structure Database: massively expanding the structural coverage of protein-sequence space with high-accuracy models. Nucleic Acids Res. 50, D439–D444 (2021).

    Article 
    PubMed Central 

    Google Scholar 

  • Callaway, E. ‘The entire protein universe’: AI predicts shape of nearly every known protein. Nature 608, 15–16 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Evans, R. et al. Protein complex prediction with AlphaFold-Multimer. Preprint at bioRxiv https://doi.org/10.1101/2021.10.04.463034 (2021).

  • Ahdritz, G. et al. OpenProteinSet: training data for structural biology at scale. In Advances in Neural Information Processing Systems (eds Oh, A. et al.) 4597-4609 (Curran Associates, 2023).

  • Paszke, A. et al. PyTorch: An Imperative Style, High-Performance Deep Learning Library. In Advances in Neural Information Processing Systems (eds Wallach, H. et al.) 8026–8037 (Curran Associates, 2019).

  • Bradbury, J. et al. JAX: composable transformations of Python+NumPy programs. GitHub github.com/google/jax (2018).

  • Rasley, J., Rajbhandari, S., Ruwase, O. & He, Y. DeepSpeed: system optimizations enable training deep learning models with over 100 billion parameters. In Proceedings of the 26th ACM SIGKDD International Conference on Knowledge Discovery & Data Mining, KDD ’20 3505–3506 (Association for Computing Machinery, 2020).

  • Charlier, B., Feydy, J., Glaunès, J., Collin, F.-D. & Durif, G. Kernel operations on the GPU, with autodiff, without memory overflows. J. Mach. Learn. Res. 22, 1–6 (2021).

    Google Scholar 

  • Falcon, W. & the PyTorch Lightning team. PyTorch Lightning (PyTorch Lightning, 2019).

  • Dao, T., Fu, D. Y., Ermon, S., Rudra, A. & Ré, C. FlashAttention: fast and memory-efficient exact attention with IO-awareness. In Advances in Neural Information Processing Systems (eds Koyejo, S. et al.) 16344–16359 (Curran Associates, 2022).

  • Mirdita, M. et al. Uniclust databases of clustered and deeply annotated protein sequences and alignments. Nucleic Acids Res. 45, D170–D176 (2017).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • wwPDB Consortium. Protein Data Bank: the single global archive for 3D macromolecular structure data. Nucleic Acids Res. 47, D520–D528 (2018).

    Article 

    Google Scholar 

  • Haas, J. ürgen et al. Continuous automated model evaluation (CAMEO) complementing the critical assessment of structure prediction in CASP12. Proteins 86, 387–398 (2018).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Mariani, V., Biasini, M., Barbato, A. & Schwede, T. lDDT: a local superposition-free score for comparing protein structures and models using distance difference tests. Bioinformatics 29, 2722–2728 (2013).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Orengo, C. A. et al. CATH—a hierarchic classification of protein domain structures. Structure 5, 1093–1108 (1997).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Sillitoe, I. et al. CATH: increased structural coverage of functional space. Nucleic Acids Res. 49, D266–D273 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Andreeva, A., Kulesha, E., Gough, J. & Murzin, A. G. The SCOP database in 2020: expanded classification of representative family and superfamily domains of known protein structures. Nucleic Acids Res. 48, D376–D382 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Saitoh, Y. et al. Structural basis for high selectivity of a rice silicon channel Lsi1. Nat. Commun. 12, 6236 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Mota, DaniellyC. A. M. et al. Structural and thermodynamic analyses of human TMED1 (p241) Golgi dynamics. Biochimie 192, 72–82 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Vaswani, A. et al. Attention is all you need. In Advances in Neural Information Processing Systems (eds Guyon, I. et al.) (Curran Associates, 2017).

  • Rabe, M. N. & Staats, C. Self-attention does not need O(n2) memory. Preprint at https://doi.org/10.48550/arXiv.2112.05682 (2021).

  • Cheng, S. et al. FastFold: Optimizing AlphaFold Training and Inference on GPU Clusters. In Proceedings of the 29th ACM SIGPLAN Annual Symposium on Principles and Practice of Parallel Programming 417–430 (Association for Computing Machinery, 2024).

  • Li, Z. et al. Uni-Fold: an open-source platform for developing protein folding models beyond AlphaFold. Preprint at bioRxiv https://doi.org/10.1101/2022.08.04.502811 (2022).

  • Kabsch, W. & Sander, C. Dictionary of protein secondary structure: pattern recognition of hydrogen-bonded and geometrical features. Science 22, 2577–2637 (1983).

    CAS 

    Google Scholar 

  • Zemla, A. LGA: a method for finding 3D similarities in protein structures. Nucleic Acids Res. 31, 3370–3374 (2003).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Marks, D. S. et al. Protein 3D structure computed from evolutionary sequence variation. PLoS ONE 6, e28766 (2011).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Sułkowska, J. I., Morcos, F., Weigt, M., Hwa, T. & Onuchic, José Genomics-aided structure prediction. Proc. Natl Acad. Sci. USA 109, 10340–10345 (2012).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Kaplan, J. et al. Scaling laws for neural language models. Preprint at https://doi.org/10.48550/arXiv.2001.08361 (2020).

  • Hoffmann, J. et al. An empirical analysis of compute-optimal large language model training. In Advances in Neural Information Processing Systems (eds Oh, A. H. et al.) 30016–30030 (NeurIPS, 2022).

  • Tay, Y. et al. Scaling laws vs model architectures: how does inductive bias influence scaling? In Findings of the Association for Computational Linguistics: EMNLP 2023 (eds Bouamor, H. et al.) 12342–12364 (Association for Computational Linguistics, 2023).

  • Lin, Z. et al. Evolutionary-scale prediction of atomic-level protein structure with a language model. Science 379, 1123–1130 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Alley, E. C., Khimulya, G., Biswas, S., AlQuraishi, M. & Church, G. M. Unified rational protein engineering with sequence-based deep representation learning. Nat. Methods 16, 1315–1322 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Chowdhury, R. et al. Single-sequence protein structure prediction using a language model and deep learning. Nat. Biotechnol. 40, 1617–1623 (2022).

  • Wu, R. et al. High-resolution de novo structure prediction from primary sequence. Preprint at bioRxiv https://doi.org/10.1101/2022.07.21.500999 (2022).

  • Singh, J., Paliwal, K., Litfin, T., Singh, J. & Zhou, Y. Predicting RNA distance-based contact maps by integrated deep learning on physics-inferred secondary structure and evolutionary-derived mutational coupling. Bioinformatics 38, 3900–3910 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Baek, M., McHugh, R., Anishchenko, I., Baker, D. & DiMaio, F. Accurate prediction of protein–nucleic acid complexes using RoseTTAFoldNA. Nat. Methods 21, 117–121 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Pearce, R., Omenn, G. S. & Zhang, Y. De novo RNA tertiary structure prediction at atomic resolution using geometric potentials from deep learning. Preprint at bioRxiv https://doi.org/10.1101/2022.05.15.491755 (2022).

  • McPartlon, M., Lai, B. & Xu, J. A deep SE(3)-equivariant model for learning inverse protein folding. Preprint at bioRxiv https://doi.org/10.1101/2022.04.15.488492 (2022).

  • McPartlon, M. & Xu, J. An end-to-end deep learning method for protein side-chain packing and inverse folding. In Proceedings of the National Academy of Sciences e2216438120 (PNAS, 2023).

  • Knox, H. L., Sinner, E. K., Townsend, C. A., Boal, A. K. & Booker, S. J. Structure of a B12-dependent radical SAM enzyme in carbapenem biosynthesis. Nature 602, 343–348 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Zhang, Y. & Skolnick, J. Scoring function for automated assessment of protein structure template quality. Proteins 57, 702–710 (2004).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Rajbhandari, S., Rasley, J., Ruwase, O. & He, Y. Zero: memory optimizations toward training trillion parameter models. In Proceedings of the International Conference for High Performance Computing, Networking, Storage and Analysis (IEEE Press, 2020).

  • Kingma, D. P. & Ba, J. Adam: a method for stochastic optimization. In 3rd International Conference on Learning Representations (eds Bengio, Y. & LeCun, Y.) (ICLR, 2015).

  • Wang, G. et al. HelixFold: an efficient implementation of AlphaFold2 using PaddlePaddle. Preprint at https://doi.org/10.48550/arXiv.2207.05477 (2022).

  • Yuan, J. et al. OneFlow: redesign the distributed deep learning framework from scratch. Preprint at https://doi.org/10.48550/arXiv.2110.15032 (2021).

  • Ovchinnikov, S. Weekend project! nerd-face So now that OpenFold weights are available. I was curious how different they are from AlphaFold weights and if they can be used for AfDesign evaluation. More specifically, if you design a protein with AlphaFold, can OpenFold predict it (and vice-versa)? (1/5). Twitter twitter.com/sokrypton/status/1551242121528520704?lang=en (2022).

  • Wei, X. et al. The α-helical cap domain of a novel esterase from gut Alistipes shahii shaping the substrate-binding pocket. J. Agric. Food Chem. 69, 6064–6072 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Carroll, B. L. et al. Caught in motion: human NTHL1 undergoes interdomain rearrangement necessary for catalysis. Nucleic Acids Res. 49, 13165–13178 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 





  • Source link

    Leave a Reply

    Your email address will not be published. Required fields are marked *