Biological sequences, including RNAs and proteins, share similarities with natural languages, enabling the application of advanced language models to various biological tasks. However, due to its flexibility and lack of experimental data, RNA is a particularly challenging biological ``language'' compared to other biological sequences like proteins. RNA multiple sequence alignments (MSAs), which align evolutionarily related RNA sequences, can greatly enhance RNA biology modeling, as evidenced by their significant roles in structure prediction and function annotation. This raises the question of whether RNA MSAs can also benefit RNA design, which remains unexplored. This paper introduces RMSAGen, a model comprising RMSA-Encoder and RMSA-Decoder, that leverages MSAs to design functional RNA sequences. RMSA-Encoder effectively extracts MSA features, enhancing performance in functional prediction and solvent accessibility prediction tasks and supporting RMSA-Decoder in accurate RNA generation. RMSAGen can design RNA sequences that effectively bind to target RNA-binding proteins, and the design performance improves with an increasing number of sequences. In addition, the ribozymes designed with structural features by RMSAGen show strong computational metrics and exhibit biological activity during gel electrophoresis. These results highlight the effectiveness of RMSAGen, establishing it as a powerful tool and a new direction for RNA design.

Inverse Protein Folding (IPF) is a critical subtask in the field of protein design, aiming to engineer amino acid sequences capable of folding correctly into a specified three-dimensional (3D) conformation. Although substantial progress has been achieved in recent years, existing methods generally rely on either backbone coordinates or molecular surface features alone, which restricts their ability to fully capture the complex chemical and geometric constraints necessary for precise sequence prediction. To address this limitation, we present DS-ProGen, a dual-structure deep language model for functional protein design, which integrates both backbone geometry and surface-level representations. By incorporating backbone coordinates as well as surface chemical and geometric descriptors into a next-amino-acid prediction paradigm, DS-ProGen is able to generate functionally relevant and structurally stable sequences while satisfying both global and local conformational constraints. On the PRIDE dataset, DS-ProGen attains the current state-of-the-art recovery rate of 61.47%, demonstrating the synergistic advantage of multi-modal structural encoding in protein design. Furthermore, DS-ProGen excels in predicting interactions with a variety of biological partners, including ligands, ions, and RNA, confirming its robust functional retention capabilities.

Jiyue Jiang, Yitao Xu, Zikang Wang, Yihan Ye, Yanruisheng Shao, Yuheng Shan, Jiuming Wang, Xiaodan Fan, Jiao Yuan, Yu Li. Proceedings of the 2025 Conference on Empirical Methods in Natural Language Processing. 2025.

MOTIVATION: As an important group of proteins discovered in phages, anti-CRISPR inhibits the activity of the immune system of bacteria (i.e. CRISPR-Cas), offering promise for gene editing and phage therapy. However, the prediction and discovery of anti-CRISPR are challenging due to their high variability and fast evolution. Existing biological studies rely on known CRISPR and anti-CRISPR pairs, which may not be practical considering the huge number. Computational methods struggle with prediction performance. To address these issues, we propose a novel deep neural network for anti-CRISPR analysis (AcrNET), which achieves significant performance. RESULTS: On both the cross-fold and cross-dataset validation, our method outperforms the state-of-the-art methods. Notably, AcrNET improves the prediction performance by at least 15% regarding the F1 score for the cross-dataset test problem comparing with state-of-art Deep Learning method. Moreover, AcrNET is the first computational method to predict the detailed anti-CRISPR classes, which may help illustrate the anti-CRISPR mechanism. Taking advantage of a Transformer protein language model ESM-1b, which was pre-trained on 250 million protein sequences, AcrNET overcomes the data scarcity problem. Extensive experiments and analysis suggest that the Transformer model feature, evolutionary feature, and local structure feature complement each other, which indicates the critical properties of anti-CRISPR proteins. AlphaFold prediction, further motif analysis, and docking experiments further demonstrate that AcrNET can capture the evolutionarily conserved pattern and the interaction between anti-CRISPR and the target implicitly. AVAILABILITY AND IMPLEMENTATION: Web server: https://proj.cse.cuhk.edu.hk/aihlab/AcrNET/. Training code and pre-trained model are available at.