Large-Scale Multi-omic Biosequence Transformers for Modeling Protein-Nucleic Acid Interactions

The transformer architecture has revolutionized bioinformatics and driven progress in the understanding and prediction of the properties of biomolecules. Almost all research on large-scale biosequence transformers has focused on one domain at a time (single-omic), usually DNA/RNA or proteins. These models have seen incredible success in downstream tasks in each domain, and have achieved particularly noteworthy breakthroughs in sequence modeling and structural modeling. However, these single-omic models are naturally incapable of efficiently modeling multi-omic tasks, one of the most biologically critical being protein-nucleic acid interactions. We present our work training the largest open-source multi-omic foundation model to date. We show that these multi-omic models (MOMs) can learn joint representations between various single-omic distributions that are emergently consistent with the Central Dogma of molecular biology despite only being trained on unlabeled biosequences. We further demonstrate that MOMs can be fine-tuned to achieve state-of-the-art results on protein-nucleic acid interaction tasks, namely predicting the change in Gibbs free energy ($\Delta G$) of the binding interaction between a given nucleic acid and protein. Remarkably, we show that multi-omic biosequence transformers emergently learn useful structural information without any \textit{a priori} structural training, allowing us to predict which protein residues are most involved in the protein-nucleic acid binding interaction. Lastly, we provide evidence that multi-omic biosequence models are in many cases superior to foundation models trained on single-omics distributions, both in performance-per-FLOP and absolute performance, suggesting a more generalized or foundational approach to building these models for biology.

@article{chen2025_2408.16245,
  title={ Large-Scale Multi-omic Biosequence Transformers for Modeling Protein-Nucleic Acid Interactions },
  author={ Sully F. Chen and Robert J. Steele and Glen M. Hocky and Beakal Lemeneh and Shivanand P. Lad and Eric K. Oermann },
  journal={arXiv preprint arXiv:2408.16245},
  year={ 2025 }
}