NACraft: Programmatic nucleic-acid aptamer design via all-atom structure-model feedback

Zhu, H.; Wang, J.; Zhao, W.; Xu, Y.; Su, H.; Wang, Q.; Yu, Y.; You, Z.; Du, G.; Heng, P. A.; Zhang, L.; Zhang, O.

doi:10.64898/2026.08.15.744087

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bioRxiv · 10.64898/2026.08.15.744087

NACraft: Programmatic nucleic-acid aptamer design via all-atom structure-model feedback

Zhu, H.·Wang, J.·Zhao, W.·Xu, Y.·Su, H.·Wang, Q.·Yu, Y.·You, Z.·Du, G.·Heng, P. A.·Zhang, L.·Zhang, O.

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Abstract

Protein-nucleic-acid interactions underpin diverse biological processes and provide a basis for molecular sensing, regulation and therapeutic intervention. However, the coupled dependence of aptamer function on nucleotide sequence, three-dimensional folding and target binding makes rational RNA and DNA binder design challenging. Here we present NACraft, a training-free and programmatic framework for all-atom nucleic-acid aptamer design based on backpropagation through structure-model feedback. By composing binding, sequence-similarity and anti-binding constraints, NACraft supports de novo generation, similarity-guided sampling and target-selective design within a unified optimization framework, without task-specific training or fine-tuning. Computational experiments showed that NACraft generated high-confidence candidates de novo across diverse protein targets, with further improvements achieved through similarity-guided design for both RNA and DNA complexes. Its target-selective design capability was further validated in silico, with 69.44% of paired candidates generated to favour the positive target EGFR over the off-target HER2. Under matched independent AlphaFold3 evaluation, NACraft achieved better performance than ODesign in 10 of 11 NA-12 targets and 17 of 20 protein target-length settings. Together, these results demonstrate the effectiveness and versatility of NACraft and extend structure-model hallucination toward programmatic nucleic-acid aptamer design. Codehttps://github.com/OTEAM-AI4S/NACraft

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Zhu, H., Wang, J., Zhao, W., Xu, Y., Su, H., Wang, Q., Yu, Y., You, Z., Du, G., Heng, P. A., Zhang, L., Zhang, O.. 2026-08-21. NACraft: Programmatic nucleic-acid aptamer design via all-atom structure-model feedback. https://doi.org/10.64898/2026.08.15.744087

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