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Generative and predictive neural networks for the design of functional RNA molecules

Author

Listed:
  • Aidan T. Riley

    (Boston University
    Boston University)

  • James M. Robson

    (Boston University
    Boston University)

  • Aiganysh Ulanova

    (Biochemistry and Molecular Biology Program Boston University
    Boston University)

  • Alexander A. Green

    (Boston University
    Boston University
    Boston University)

Abstract

RNA is a remarkably versatile molecule that has been engineered for applications in therapeutics, diagnostics, and in vivo information-processing systems. However, the complex relationship between the sequence, structure, and function of RNA often necessitates extensive experimental screening of candidate sequences. Here we present a generalized, efficient neural network architecture that utilizes the sequence and structure of RNA molecules (SANDSTORM) to inform functional predictions across a diverse range of settings. We pair these predictive models with generative adversarial RNA design networks (GARDN), allowing the generative modelling of a diverse range of functional RNA molecules with targeted experimental attributes. This approach enables the design of novel sequence candidates that outperform those encountered during training or returned by classical thermodynamic algorithms, and can be deployed using as few as 384 example sequences. SANDSTORM and GARDN thus represent powerful new predictive and generative tools for the development of RNA molecules with improved function.

Suggested Citation

  • Aidan T. Riley & James M. Robson & Aiganysh Ulanova & Alexander A. Green, 2025. "Generative and predictive neural networks for the design of functional RNA molecules," Nature Communications, Nature, vol. 16(1), pages 1-17, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-59389-8
    DOI: 10.1038/s41467-025-59389-8
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    1. Brent Townshend & Joy S. Xiang & Gabriel Manzanarez & Eric J. Hayden & Christina D. Smolke, 2021. "A multiplexed, automated evolution pipeline enables scalable discovery and characterization of biosensors," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    2. Jaswinder Singh & Jack Hanson & Kuldip Paliwal & Yaoqi Zhou, 2019. "RNA secondary structure prediction using an ensemble of two-dimensional deep neural networks and transfer learning," Nature Communications, Nature, vol. 10(1), pages 1-13, December.
    3. Kengo Sato & Manato Akiyama & Yasubumi Sakakibara, 2021. "RNA secondary structure prediction using deep learning with thermodynamic integration," Nature Communications, Nature, vol. 12(1), pages 1-9, December.
    4. Kathrin Leppek & Gun Woo Byeon & Wipapat Kladwang & Hannah K. Wayment-Steele & Craig H. Kerr & Adele F. Xu & Do Soon Kim & Ved V. Topkar & Christian Choe & Daphna Rothschild & Gerald C. Tiu & Roger We, 2022. "Combinatorial optimization of mRNA structure, stability, and translation for RNA-based therapeutics," Nature Communications, Nature, vol. 13(1), pages 1-22, December.
    5. Jacqueline A. Valeri & Katherine M. Collins & Pradeep Ramesh & Miguel A. Alcantar & Bianca A. Lepe & Timothy K. Lu & Diogo M. Camacho, 2020. "Sequence-to-function deep learning frameworks for engineered riboregulators," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
    6. Yu Zhou & Peike Sheng & Jiayi Li & Yudan Li & Mingyi Xie & Alexander A. Green, 2024. "Conditional RNA interference in mammalian cells via RNA transactivation," Nature Communications, Nature, vol. 15(1), pages 1-10, December.
    7. Cheri M. Ackerman & Cameron Myhrvold & Sri Gowtham Thakku & Catherine A. Freije & Hayden C. Metsky & David K. Yang & Simon H. Ye & Chloe K. Boehm & Tinna-Sólveig F. Kosoko-Thoroddsen & Jared Kehe & Ti, 2020. "Massively multiplexed nucleic acid detection with Cas13," Nature, Nature, vol. 582(7811), pages 277-282, June.
    8. Joy S. Xiang & Matias Kaplan & Peter Dykstra & Michaela Hinks & Maureen McKeague & Christina D. Smolke, 2019. "Massively parallel RNA device engineering in mammalian cells with RNA-Seq," Nature Communications, Nature, vol. 10(1), pages 1-16, December.
    9. Yongjun Qian & Jiayun Li & Shengli Zhao & Elizabeth A. Matthews & Michael Adoff & Weixin Zhong & Xu An & Michele Yeo & Christine Park & Xiaolu Yang & Bor-Shuen Wang & Derek G. Southwell & Z. Josh Huan, 2022. "Programmable RNA sensing for cell monitoring and manipulation," Nature, Nature, vol. 610(7933), pages 713-721, October.
    10. James Chappell & Alexandra Westbrook & Matthew Verosloff & Julius B. Lucks, 2017. "Computational design of small transcription activating RNAs for versatile and dynamic gene regulation," Nature Communications, Nature, vol. 8(1), pages 1-12, December.
    11. Nicolaas M. Angenent-Mari & Alexander S. Garruss & Luis R. Soenksen & George Church & James J. Collins, 2020. "A deep learning approach to programmable RNA switches," Nature Communications, Nature, vol. 11(1), pages 1-12, December.
    12. He Zhang & Liang Zhang & Ang Lin & Congcong Xu & Ziyu Li & Kaibo Liu & Boxiang Liu & Xiaopin Ma & Fanfan Zhao & Huiling Jiang & Chunxiu Chen & Haifa Shen & Hangwen Li & David H. Mathews & Yujian Zhang, 2023. "Algorithm for optimized mRNA design improves stability and immunogenicity," Nature, Nature, vol. 621(7978), pages 396-403, September.
    13. Yang Cao & Huachun Liu & Shannon S. Lu & Krysten A. Jones & Anitha P. Govind & Okunola Jeyifous & Christine Q. Simmons & Negar Tabatabaei & William N. Green & Jimmy. L. Holder & Soroush Tahmasebi & Al, 2023. "RNA-based translation activators for targeted gene upregulation," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    14. Hui Ning & Gan Liu & Lei Li & Qiang Liu & Huiya Huang & Zhen Xie, 2023. "Rational design of microRNA-responsive switch for programmable translational control in mammalian cells," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
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