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Cited by 2RNA and protein synthesis mechanismsProtein Structure and DynamicsRNA regulation and disease

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Structure-alignment-driven cross-graph modeling for functional RNA design

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Wang, Shengfan, Wang, Jun, Liu, Xiaojian, Zhu, Weimin, Huang, Jiaqi, Xue, Yiming, Yan, Junchi, Shen, Hong-Bin, Song, Jie, Pan, Xiaoyong·2026·Nature Computational Science
DOI 10.1038/s43588-026-01029-2

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Abstract

RNAs are critical for biological processes, and their functions are closely tied to their three-dimensional structures. The design of RNA sequences that fold into target three-dimensional structures is a complex challenge due to the dynamic and unstable nature of RNA structures. Here we present an RNA design approach, AlignIF, that leverages multiple structure alignment with cross-graph modeling and carefully hand-designed features to capture evolutionarily conserved structural patterns at the structural level, facilitating RNA sequence design. AlignIF outperforms existing state-of-the-art methods in test sets. Notably, it enables the design of entire RNA families rather than being restricted to recapitulating native sequences. Furthermore, AlignIF successfully designs functional RNA fluorescent aptamers and self-cleaving ribozymes that exhibit measurable activity without requiring any postdesign filtering. For Mango-I, two of ten designed aptamers showed enhanced fluorescence, and two others exhibited improved binding affinity compared with the wild type. For the more challenging iMango-III, all designs were fluorescent, including one with a sequence identity of ~30% relative to the wild type. The results highlight the potential of AlignIF for functional RNA engineering.

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Metadata

Authors
Wang, S., Wang, J., Liu, X., Zhu, W., Huang, J., Xue, Y., Yan, J., Shen, H.-B., Song, J., & Pan, X.
Affiliations
Shanghai Jiao Tong University (CN)
Corresponding author
  • Shen, Hong-Bin
  • Song, Jie
  • Pan, Xiaoyong
ORCID
Venue
Nature Computational Science
Publisher
Springer Science and Business Media LLC
Published
2026-07-30
Volume
6
Issue
8
Pages
826-841
ISSN
2662-8457 (ISSN-L)
DOI
10.1038/s43588-026-01029-2
OpenAlex
W7171784881
Cited by
2
References
3
Citations by year
2026: 2
FWCI
4.18
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Computational Science (publishedVersion)
  • Research Square (acceptedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • National Natural Science Foundation of China (62473257)
  • Science and Technology Commission of Shanghai Municipality (24ZR1435300, 22511104100)
  • Natural Science Foundation of Zhejiang Province (YXD23B0301)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA regulation and disease
Keywords
RNA sequence design, RNA structure alignment, RNA folding, fluorescent aptamers, self-cleaving ribozymes, RNA families
MeSH terms
Base Sequence, Models, Molecular, Nucleic Acid Conformation, RNA, RNA, Catalytic, Sequence Alignment, Aptamers, Nucleotide

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