De novo design of functional RNAs through higher-order interactions
- 1Wuhan University
Abstract
Designing RNA sequences that reliably adopt functional three-dimensional structures remains a central challenge in RNA engineering because folding depends on cooperative interactions beyond canonical base pairing. Here we present DS3dRNA, an interaction-based framework for de novo RNA sequence design that combines a three-body statistical potential with physics-guided sequence sampling and supports design against multiple conformations. Across the evaluated benchmarks, DS3dRNA outperformed representative RNA inverse-design methods in native-sequence recovery and agreement between predicted and target structures. Energy-sequence-quality analyses further showed that lower design energies generally accompanied higher sequence recovery and macro-averaged F1 scores (MacroF1). Experimentally tested Mango II designs retained high-affinity fluorogenic activity, and five twister ribozyme designs yielded mean endpoint cleavage fractions of 37.7-50.6%, compared with 23.5% for the wild type. These results establish explicit higher-order interaction scoring as a complementary approach to emerging data-driven RNA design methods and provide a framework for designing functional RNAs from experimental or predicted structural ensembles.
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BibTeX
@misc{yuan2026novo,
title = {{De novo design of functional RNAs through higher-order interactions}},
author = {T. Yuan and D. Wang and X.-L. Chen and H.-L. Tao and C.-C. Z. Zheng and X.-C. Zhao and Y.-L. Tan and X.-H. Zhang and Z.-J. Tan},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.26.754601},
url = {https://www.biorxiv.org/content/10.64898/2026.09.26.754601v1},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - De novo design of functional RNAs through higher-order interactions
AU - T. Yuan
AU - D. Wang
AU - X.-L. Chen
AU - H.-L. Tao
AU - C.-C. Z. Zheng
AU - X.-C. Zhao
AU - Y.-L. Tan
AU - X.-H. Zhang
AU - Z.-J. Tan
PY - 2026
DA - 2026/09/26
PB - bioRxiv
DO - 10.64898/2026.09.26.754601
UR - https://www.biorxiv.org/content/10.64898/2026.09.26.754601v1
AB - Designing RNA sequences that reliably adopt functional three-dimensional structures remains a central challenge in RNA engineering because folding depends on cooperative interactions beyond canonical base pairing. Here we present DS3dRNA, an interaction-based framework for de novo RNA sequence design that combines a three-body statistical potential with physics-guided sequence sampling and supports design against multiple conformations. Across the evaluated benchmarks, DS3dRNA outperformed representative RNA inverse-design methods in native-sequence recovery and agreement between predicted and target structures. Energy-sequence-quality analyses further showed that lower design energies generally accompanied higher sequence recovery and macro-averaged F1 scores (MacroF1). Experimentally tested Mango II designs retained high-affinity fluorogenic activity, and five twister ribozyme designs yielded mean endpoint cleavage fractions of 37.7-50.6%, compared with 23.5% for the wild type. These results establish explicit higher-order interaction scoring as a complementary approach to emerging data-driven RNA design methods and provide a framework for designing functional RNAs from experimental or predicted structural ensembles.
ER -