Single-sequence protein-RNA complex structure prediction by geometric attention-enabled pairing of biological language models

Ground-breaking progress has been made in structure prediction of biomolecular assemblies, including the recent breakthrough of AlphaFold 3. However, it remains challenging for AlphaFold 3 and other state-of-the-art deep learning-based methods to accurately predict protein-RNA complex structures, in part due to the limited availability of evolutionary and structural information related to protein-RNA interactions that are used as inputs to the existing approaches. Here, we introduce ProRNA3D-single, a new deep-learning framework for protein-RNA complex structure prediction with only single-sequence input. Using a novel geometric attention-enabled pairing of biological language models of protein and RNA, a previously unexplored avenue, ProRNA3D-single enables the prediction of interatomic protein-RNA interaction maps, which are then transformed into multi-scale geometric restraints for modeling 3D structures of protein-RNA complexes via geometry optimization. Benchmark tests show that ProRNA3D-single convincingly outperforms current state-of-the-art methods including AlphaFold 3, particularly when evolutionary information is limited; and exhibits remarkable robustness and performance resilience by attaining better accuracy with only single-sequence input than what most methods can achieve even with explicit evolutionary information. Freely available at https://github.com/Bhattacharya-Lab/ProRNA3D-single, ProRNA3D-single should be broadly useful for modeling 3D structures of protein-RNA complexes at scale, regardless of the availability of evolutionary information.