Ab initio RNA structure prediction with composite language model and denoised end-to-end learning

RNA structures are essential for understanding their biological functions and developing RNA-targeted therapeutics. However, accurate RNA structure prediction from sequence remains a crucial challenge. We introduce DRfold2, a deep learning framework that integrates a novel pre-trained RNA Composite Language Model (RCLM) with a denoising structure module for end-to-end RNA structure prediction. DRfold2 achieves superior performance in both global topology and secondary structure predictions over other state-of-the-art approaches across multiple benchmark tests. Detailed analyses reveal that the improvements primarily stem from the RCLM’s ability to capture co-evolutionary pattern and the effective denoising process, leading to a more than 100% increase in contact prediction precision compared to existing methods. Furthermore, DRfold2 demonstrates high complementarity with AlphaFold3, achieving statistically significant accuracy gains when integrated into our optimization framework. By uniquely combining composite language modeling, denoise-based end-to-end learning, and deep learning-guided post-optimization, DRfold2 establishes a distinct direction for advancing ab initio RNA structure prediction.