IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v16y2025i1d10.1038_s41467-025-58250-2.html
   My bibliography  Save this article

Protein sequence modelling with Bayesian flow networks

Author

Listed:
  • Timothy Atkinson

    (InstaDeep)

  • Thomas D. Barrett

    (InstaDeep)

  • Scott Cameron

    (InstaDeep)

  • Bora Guloglu

    (InstaDeep)

  • Matthew Greenig

    (InstaDeep)

  • Charlie B. Tan

    (InstaDeep)

  • Louis Robinson

    (InstaDeep)

  • Alex Graves

    (InstaDeep)

  • Liviu Copoiu

    (InstaDeep)

  • Alexandre Laterre

    (InstaDeep)

Abstract

Exploring the vast and largely uncharted territory of amino acid sequences is crucial for understanding complex protein functions and the engineering of novel therapeutic proteins. Whilst generative machine learning has advanced protein sequence modelling, no existing approach is proficient in both unconditional and conditional generation. In this work, we propose that Bayesian Flow Networks (BFNs), a recently introduced framework for generative modelling, can address these challenges. We present ProtBFN, a 650M parameter model trained on protein sequences curated from UniProtKB, which generates natural-like, diverse, structurally coherent, and novel protein sequences, significantly outperforming leading autoregressive and discrete diffusion models. Further, we fine-tune ProtBFN on heavy chains from the Observed Antibody Space to obtain an antibody-specific model, AbBFN, which we use to evaluate zero-shot conditional generation capabilities. AbBFN is found to be competitive with or better than antibody-specific BERT-style models when applied to predicting individual framework or complimentary determining regions.

Suggested Citation

  • Timothy Atkinson & Thomas D. Barrett & Scott Cameron & Bora Guloglu & Matthew Greenig & Charlie B. Tan & Louis Robinson & Alex Graves & Liviu Copoiu & Alexandre Laterre, 2025. "Protein sequence modelling with Bayesian flow networks," Nature Communications, Nature, vol. 16(1), pages 1-14, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-58250-2
    DOI: 10.1038/s41467-025-58250-2
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-025-58250-2
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-025-58250-2?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Joseph L. Watson & David Juergens & Nathaniel R. Bennett & Brian L. Trippe & Jason Yim & Helen E. Eisenach & Woody Ahern & Andrew J. Borst & Robert J. Ragotte & Lukas F. Milles & Basile I. M. Wicky & , 2023. "De novo design of protein structure and function with RFdiffusion," Nature, Nature, vol. 620(7976), pages 1089-1100, August.
    2. Josh Abramson & Jonas Adler & Jack Dunger & Richard Evans & Tim Green & Alexander Pritzel & Olaf Ronneberger & Lindsay Willmore & Andrew J. Ballard & Joshua Bambrick & Sebastian W. Bodenstein & David , 2024. "Addendum: Accurate structure prediction of biomolecular interactions with AlphaFold 3," Nature, Nature, vol. 636(8042), pages 4-4, December.
    3. Noelia Ferruz & Steffen Schmidt & Birte Höcker, 2022. "ProtGPT2 is a deep unsupervised language model for protein design," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    4. Andy M. Lau & Shaun M. Kandathil & David T. Jones, 2023. "Merizo: a rapid and accurate protein domain segmentation method using invariant point attention," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    5. Josh Abramson & Jonas Adler & Jack Dunger & Richard Evans & Tim Green & Alexander Pritzel & Olaf Ronneberger & Lindsay Willmore & Andrew J. Ballard & Joshua Bambrick & Sebastian W. Bodenstein & David , 2024. "Accurate structure prediction of biomolecular interactions with AlphaFold 3," Nature, Nature, vol. 630(8016), pages 493-500, June.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Sophia Vincoff & Shrey Goel & Kseniia Kholina & Rishab Pulugurta & Pranay Vure & Pranam Chatterjee, 2025. "FusOn-pLM: a fusion oncoprotein-specific language model via adjusted rate masking," Nature Communications, Nature, vol. 16(1), pages 1-11, December.
    2. Xin Yong & Guowen Jia & Qin Yang & Chunzhuang Zhou & Sitao Zhang & Huaqing Deng & Daniel D. Billadeau & Zhaoming Su & Da Jia, 2025. "Cryo-EM structure of the BLOC-3 complex provides insights into the pathogenesis of Hermansky-Pudlak syndrome," Nature Communications, Nature, vol. 16(1), pages 1-15, December.
    3. William J. Nicolas & Anna Shiriaeva & Michael W. Martynowycz & Angus C. Grey & Yasmeen N. Ruma & Paul J. Donaldson & Tamir Gonen, 2025. "Structure of the lens MP20 mediated adhesive junction," Nature Communications, Nature, vol. 16(1), pages 1-10, December.
    4. Gašper Šolinc & Marija Srnko & Franci Merzel & Ana Crnković & Mirijam Kozorog & Marjetka Podobnik & Gregor Anderluh, 2025. "Cryo-EM structures of a protein pore reveal a cluster of cholesterol molecules and diverse roles of membrane lipids," Nature Communications, Nature, vol. 16(1), pages 1-11, December.
    5. Tae-Kyeong Jeong & R. Ciaran MacKenzie Frater & Jongha Yoon & Anja Groth & Ji-Joon Song, 2025. "CODANIN-1 sequesters ASF1 by using a histone H3 mimic helix to regulate the histone supply," Nature Communications, Nature, vol. 16(1), pages 1-17, December.
    6. Juan G. Carvajal-Patiño & Vincent Mallet & David Becerra & Luis Fernando Niño Vasquez & Carlos Oliver & Jérôme Waldispühl, 2025. "RNAmigos2: accelerated structure-based RNA virtual screening with deep graph learning," Nature Communications, Nature, vol. 16(1), pages 1-12, December.
    7. James Hodgkinson-Bean & Rafael Ayala & Nadishka Jayawardena & Georgia L. Rutter & Bridget N. J. Watson & David Mayo-Muñoz & James Keal & Peter C. Fineran & Matthias Wolf & Mihnea Bostina, 2025. "Global structural survey of the flagellotropic myophage φTE infecting agricultural pathogen Pectobacterium atrosepticum," Nature Communications, Nature, vol. 16(1), pages 1-17, December.
    8. Wenkai Chen & Xueying Xu & Zhidan Zeng & Mingsen Zhou & Jiying Chen & Guangfu Hu & Anfu Shen & Dapeng Li & Liu Xiangjiang, 2025. "The role of pyruvate dehydrogenase in the lifespan determination of daphnids," Nature Communications, Nature, vol. 16(1), pages 1-14, December.
    9. John R. Horton & Meigen Yu & Jujun Zhou & Melody Tran & Rithvi R. Anakal & Yue Lu & Robert M. Blumenthal & Xiaotian Zhang & Yun Huang & Xing Zhang & Xiaodong Cheng, 2025. "Multimeric transcription factor BCL11A utilizes two zinc-finger tandem arrays to bind clustered short sequence motifs," Nature Communications, Nature, vol. 16(1), pages 1-15, December.
    10. Chaoming Wang & Sichao He & Shouwei Luo & Yuxiang Huan & Si Wu, 2025. "Integrating physical units into high-performance AI-driven scientific computing," Nature Communications, Nature, vol. 16(1), pages 1-14, December.
    11. Wen Yang & Man Feng & Kuohai Yu & Jie Cao & Guangxian Cui & Yumei Zhang & Huiru Peng & Yingyin Yao & Zhaorong Hu & Zhongfu Ni & Feng Qin & Fuminori Takahashi & Qixin Sun & Mingming Xin, 2025. "The TaCLE24b peptide signaling cascade modulates lateral root development and drought tolerance in wheat," Nature Communications, Nature, vol. 16(1), pages 1-12, December.
    12. Na Jiang & Hekun Yang & Yi Lei & Weida Qin & Huifang Xiong & Kuan Chen & Kunrong Mei & Gongyu Li & Xin Mu & Ruibing Chen, 2025. "Characterization of dsRNA binding proteins through solubility analysis identifies ZNF385A as a dsRNA homeostasis regulator," Nature Communications, Nature, vol. 16(1), pages 1-19, December.
    13. Bing Wang & Nelly Said & Tarek Hilal & Mark Finazzo & Markus C. Wahl & Irina Artsimovitch, 2025. "Nucleotide-induced hyper-oligomerization inactivates transcription termination factor ρ," Nature Communications, Nature, vol. 16(1), pages 1-16, December.
    14. Xiaofei Jiao & Zhongyang Liang & Jiwei Li & Long Bai & Jun Xu & Yidan Liu & Lin-Yu Lu, 2025. "Aberrant activation of chromosome asynapsis checkpoint triggers oocyte elimination," Nature Communications, Nature, vol. 16(1), pages 1-15, December.
    15. Yu Wang & Sen Wang & Yuanyuan Chen & Chunlan Xie & Haibo Xu & Yunhua Lin & Ranxun Lin & Wanlin Zeng & Xuan Chen & Xinyi Nie & Shihua Wang, 2025. "The role of Npt1 in regulating antifungal protein activity in filamentous fungi," Nature Communications, Nature, vol. 16(1), pages 1-20, December.
    16. Samantha F. Sedor & Sichen Shao, 2025. "Mechanism of ASF1 engagement by CDAN1," Nature Communications, Nature, vol. 16(1), pages 1-13, December.
    17. Ian Y. Yen & Gregory B. Whitfield & John L. Rubinstein & Lori L. Burrows & Yves V. Brun & P. Lynne Howell, 2025. "Conformational changes in the motor ATPase CpaF facilitate a rotary mechanism of Tad pilus assembly," Nature Communications, Nature, vol. 16(1), pages 1-19, December.
    18. Qi Gao & Florian W. Hofer & Sebastian Filbeck & Bram J. A. Vermeulen & Martin Würtz & Annett Neuner & Charlotte Kaplan & Maja Zezlina & Cornelia Sala & Hyesu Shin & Oliver J. Gruss & Elmar Schiebel & , 2025. "Structural mechanisms for centrosomal recruitment and organization of the microtubule nucleator γ-TuRC," Nature Communications, Nature, vol. 16(1), pages 1-23, December.
    19. Tongqing Li & Steven E. Stayrook & Wenxue Li & Yueyue Wang & Hengyi Li & Jianan Zhang & Yansheng Liu & Daryl E. Klein, 2025. "Crystal structure of Isthmin-1 and reassessment of its functional role in pre-adipocyte signaling," Nature Communications, Nature, vol. 16(1), pages 1-11, December.
    20. Tianyang Zhao & Kuipei Jin & Xiaodong Wang & Xiong Su & Youjun Wang & Mingming Gao & Wen Luo & Hongyuan Yang & Zhongzhou Yang, 2025. "GPAT4 sustains endoplasmic reticulum homeostasis in endocardial cells and safeguards heart development," Nature Communications, Nature, vol. 16(1), pages 1-14, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-58250-2. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.