IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v16y2025i1d10.1038_s41467-025-59940-7.html
   My bibliography  Save this article

Cyclic peptide structure prediction and design using AlphaFold2

Author

Listed:
  • Stephen A. Rettie

    (University of Washington
    University of Washington)

  • Katelyn V. Campbell

    (University of Washington
    University of Washington)

  • Asim K. Bera

    (University of Washington)

  • Alex Kang

    (University of Washington)

  • Simon Kozlov

    (Massachusetts Institute of Technology)

  • Yensi Flores Bueso

    (University of Washington
    University of Washington
    University of Washington
    University College Cork)

  • Joshmyn Cruz

    (University of Washington)

  • Maggie Ahlrichs

    (University of Washington)

  • Suna Cheng

    (University of Washington)

  • Stacey R. Gerben

    (University of Washington)

  • Mila Lamb

    (University of Washington)

  • Analisa Murray

    (University of Washington)

  • Victor Adebomi

    (University of Washington
    Massachusetts Institute of Technology)

  • Guangfeng Zhou

    (University of Washington
    University of Washington)

  • Frank DiMaio

    (University of Washington
    University of Washington)

  • Sergey Ovchinnikov

    (Massachusetts Institute of Technology)

  • Gaurav Bhardwaj

    (University of Washington
    University of Washington
    University of Washington)

Abstract

Small cyclic peptides have gained significant traction as a therapeutic modality; however, the development of deep learning methods for accurately designing such peptides has been slow, mostly due to the lack of sufficiently large training sets. Here, we introduce AfCycDesign, a deep learning approach for accurate structure prediction, sequence redesign, and de novo hallucination of cyclic peptides. Using AfCycDesign, we identified over 10,000 structurally-diverse designs predicted to fold into the designed structures with high confidence. X-ray crystal structures for eight tested de novo designed sequences match very closely with the design models (RMSD

Suggested Citation

  • Stephen A. Rettie & Katelyn V. Campbell & Asim K. Bera & Alex Kang & Simon Kozlov & Yensi Flores Bueso & Joshmyn Cruz & Maggie Ahlrichs & Suna Cheng & Stacey R. Gerben & Mila Lamb & Analisa Murray & V, 2025. "Cyclic peptide structure prediction and design using AlphaFold2," Nature Communications, Nature, vol. 16(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-59940-7
    DOI: 10.1038/s41467-025-59940-7
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-025-59940-7
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-025-59940-7?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. Pablo Gainza & Sarah Wehrle & Alexandra Hall-Beauvais & Anthony Marchand & Andreas Scheck & Zander Harteveld & Stephen Buckley & Dongchun Ni & Shuguang Tan & Freyr Sverrisson & Casper Goverde & Prisci, 2023. "De novo design of protein interactions with learned surface fingerprints," Nature, Nature, vol. 617(7959), pages 176-184, May.
    2. Kathryn Tunyasuvunakool & Jonas Adler & Zachary Wu & Tim Green & Michal Zielinski & Augustin Žídek & Alex Bridgland & Andrew Cowie & Clemens Meyer & Agata Laydon & Sameer Velankar & Gerard J. Kleywegt, 2021. "Highly accurate protein structure prediction for the human proteome," Nature, Nature, vol. 596(7873), pages 590-596, August.
    3. Longxing Cao & Brian Coventry & Inna Goreshnik & Buwei Huang & William Sheffler & Joon Sung Park & Kevin M. Jude & Iva Marković & Rameshwar U. Kadam & Koen H. G. Verschueren & Kenneth Verstraete & Sco, 2022. "Design of protein-binding proteins from the target structure alone," Nature, Nature, vol. 605(7910), pages 551-560, May.
    4. Ivan Anishchenko & Samuel J. Pellock & Tamuka M. Chidyausiku & Theresa A. Ramelot & Sergey Ovchinnikov & Jingzhou Hao & Khushboo Bafna & Christoffer Norn & Alex Kang & Asim K. Bera & Frank DiMaio & La, 2021. "De novo protein design by deep network hallucination," Nature, Nature, vol. 600(7889), pages 547-552, 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. "Addendum: Accurate structure prediction of biomolecular interactions with AlphaFold 3," Nature, Nature, vol. 636(8042), pages 4-4, December.
    6. Arun Chandramohan & Hubert Josien & Tsz Ying Yuen & Ruchia Duggal & Diana Spiegelberg & Lin Yan & Yu-Chi Angela Juang & Lan Ge & Pietro G. Aronica & Hung Yi Kristal Kaan & Yee Hwee Lim & Andrea Peier , 2024. "Design-rules for stapled peptides with in vivo activity and their application to Mdm2/X antagonists," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    7. John Jumper & Richard Evans & Alexander Pritzel & Tim Green & Michael Figurnov & Olaf Ronneberger & Kathryn Tunyasuvunakool & Russ Bates & Augustin Žídek & Anna Potapenko & Alex Bridgland & Clemens Me, 2021. "Highly accurate protein structure prediction with AlphaFold," Nature, Nature, vol. 596(7873), pages 583-589, August.
    8. 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.
    9. Gaurav Bhardwaj & Vikram Khipple Mulligan & Christopher D. Bahl & Jason M. Gilmore & Peta J. Harvey & Olivier Cheneval & Garry W. Buchko & Surya V. S. R. K. Pulavarti & Quentin Kaas & Alexander Eletsk, 2016. "Accurate de novo design of hyperstable constrained peptides," Nature, Nature, vol. 538(7625), pages 329-335, October.
    10. Tomer Tsaban & Julia K. Varga & Orly Avraham & Ziv Ben-Aharon & Alisa Khramushin & Ora Schueler-Furman, 2022. "Harnessing protein folding neural networks for peptide–protein docking," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    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. Pantelis Livanos & Choy Kriechbaum & Sophia Remers & Arvid Herrmann & Sabine Müller, 2025. "Kinesin-12 POK2 polarization is a prerequisite for a fully functional division site and aids cell plate positioning," Nature Communications, Nature, vol. 16(1), pages 1-17, 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. Julian O. Streit & Sammy H. S. Chan & Saifu Daya & John Christodoulou, 2025. "Rational design of 19F NMR labelling sites to probe protein structure and interactions," Nature Communications, Nature, vol. 16(1), pages 1-15, December.
    4. 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.
    5. Melissa V. Gammons & Elsa Franco-Echevarría & Tie-Mei Li & Trevor J. Rutherford & Miha Renko & Christopher Batters & Mariann Bienz, 2025. "Wnt signalosome assembly is governed by conformational flexibility of Axin and by the AP2 clathrin adaptor," Nature Communications, Nature, vol. 16(1), pages 1-21, December.
    6. Nathaniel R. Bennett & Brian Coventry & Inna Goreshnik & Buwei Huang & Aza Allen & Dionne Vafeados & Ying Po Peng & Justas Dauparas & Minkyung Baek & Lance Stewart & Frank DiMaio & Steven Munck & Savv, 2023. "Improving de novo protein binder design with deep learning," Nature Communications, Nature, vol. 14(1), pages 1-9, December.
    7. Ji Huang & Liang Tong, 2025. "Molecular insights into the overall architecture of human rixosome," Nature Communications, Nature, vol. 16(1), pages 1-12, December.
    8. Z. Faidon Brotzakis & Shengyu Zhang & Mhd Hussein Murtada & Michele Vendruscolo, 2025. "AlphaFold prediction of structural ensembles of disordered proteins," Nature Communications, Nature, vol. 16(1), pages 1-9, December.
    9. Haaris A. Safdari & Martino Morici & Ana Sanchez-Castro & Andrea Dallapè & Helge Paternoga & Anna Maria Giuliodori & Attilio Fabbretti & Pohl Milón & Daniel N. Wilson, 2025. "The translation inhibitors kasugamycin, edeine and GE81112 target distinct steps during 30S initiation complex formation," Nature Communications, Nature, vol. 16(1), pages 1-12, December.
    10. Jane Dudley-Fraser & Diego Esposito & Katherine A. McPhie & Coltrane Morley-Williams & Tania Auchynnikava & Katrin Rittinger, 2025. "Identification of RING E3 pseudoligases in the TRIM protein family," Nature Communications, Nature, vol. 16(1), pages 1-15, December.
    11. 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.
    12. 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.
    13. 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.
    14. 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.
    15. 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.
    16. Betz, Ulrich A.K. & Arora, Loukik & Assal, Reem A. & Azevedo, Hatylas & Baldwin, Jeremy & Becker, Michael S. & Bostock, Stefan & Cheng, Vinton & Egle, Tobias & Ferrari, Nicola & Schneider-Futschik, El, 2023. "Game changers in science and technology - now and beyond," Technological Forecasting and Social Change, Elsevier, vol. 193(C).
    17. Ruifang Ma & Bowen Du & Chen Shi & Lei Wang & Fuxing Zeng & Jie Han & Huiyi Guan & Yong Wang & Kaige Yan, 2025. "Molecular basis for the regulation of human phosphorylase kinase by phosphorylation and Ca2+," Nature Communications, Nature, vol. 16(1), pages 1-13, December.
    18. Tanmoy Paul & Chunli Yan & Jina Yu & Susan E. Tsutakawa & John A. Tainer & Dong Wang & Ivaylo Ivanov, 2025. "Molecular model of TFIIH recruitment to the transcription-coupled repair machinery," Nature Communications, Nature, vol. 16(1), pages 1-17, December.
    19. Julien Herrou & Laetitia My & Caroline L. Monteil & Marine Bergot & Rikesh Jain & Emmanuelle Martinez & Tâm Mignot, 2025. "Tad pili with adaptable tips mediate contact-dependent killing during bacterial predation," Nature Communications, Nature, vol. 16(1), pages 1-17, December.
    20. Tamuka M. Chidyausiku & Soraia R. Mendes & Jason C. Klima & Marta Nadal & Ulrich Eckhard & Jorge Roel-Touris & Scott Houliston & Tibisay Guevara & Hugh K. Haddox & Adam Moyer & Cheryl H. Arrowsmith & , 2022. "De novo design of immunoglobulin-like domains," Nature Communications, Nature, vol. 13(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_s41467-025-59940-7. 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.