Accurate de novo sequencing of the modified proteome with OmniNovo

preprint · arXiv · 2025

preprint · arXiv · 2025. Yuhan Chen et al. Post-translational modifications (PTMs) serve as a dynamic chemical language regulating protein function, yet…
Date 2025-12-13
Type preprint
Venue arXiv
Publisher arXiv
Contribution algorithm
DOI 10.48550/arXiv.2512.12272
Citations (OpenAlex) 0

Abstract

Post-translational modifications (PTMs) serve as a dynamic chemical language regulating protein function, yet current proteomic methods remain blind to a vast portion of the modified proteome. Standard database search algorithms suffer from a combinatorial explosion of search spaces, limiting the identification of uncharacterized or complex modifications. Here we introduce OmniNovo, a unified deep learning framework for reference-free sequencing of unmodified and modified peptides directly from tandem mass spectra. Unlike existing tools restricted to specific modification types, OmniNovo learns universal fragmentation rules to decipher diverse PTMs within a single coherent model. By integrating a mass-constrained decoding algorithm with rigorous false discovery rate estimation, OmniNovo achieves state-of-the-art accuracy, identifying 51\% more peptides than standard approaches at a 1\% false discovery rate. Crucially, the model generalizes to biological sites unseen during training, illuminating the dark matter of the proteome and enabling unbiased comprehensive analysis of cellular regulation.

Authors

  1. Yuhan Chen · Shanghai Artificial Intelligence Laboratory, Tongji University
  2. Shang Qu · Shanghai Artificial Intelligence Laboratory, Tsinghua University
  3. Zhiqiang Gao · Shanghai Artificial Intelligence Laboratory
  4. Yuejin Yang · Fudan University, Shanghai Artificial Intelligence Laboratory
  5. Xiang Zhang (Shanghai AI Lab) · Fudan University, Shanghai Artificial Intelligence Laboratory, University of British Columbia
  6. Sheng Xu · Fudan University, Shanghai Artificial Intelligence Laboratory
  7. Xinjie Mao · Shanghai Artificial Intelligence Laboratory, Shanghai Innovation Institute, Westlake University
  8. Liujia Qian · Westlake University
  9. Jiaqi Wei · Shanghai Artificial Intelligence Laboratory, Zhejiang University
  10. Zijie Qiu · Fudan University, Shanghai Artificial Intelligence Laboratory
  11. Chenyu You · Stony Brook University
  12. Lei Bai · Shanghai Artificial Intelligence Laboratory
  13. Ning Ding · Shanghai Artificial Intelligence Laboratory, Tsinghua University
  14. Tiannan Guo · Westlake Institute for Advanced Study, Westlake University
  15. Bowen Zhou · Shanghai Artificial Intelligence Laboratory, Tsinghua University
  16. Siqi Sun · Fudan University, Shanghai Artificial Intelligence Laboratory

Methods and tools

Data used

  • A protein phosphatase network controls the temporal and spatial dynamics of differentiation commitment in human epidermi (as deposited) · PXD003281
  • An impaired respiratory electron chain triggers down-regulation of the energy metabolism and de-ubiquitination of solute (as deposited) · PXD002425
  • Analysis of human acetylation stoichiometry defines mechanistic constraints on protein regulation (as deposited) · PXD009994
  • Analysis of the ubiquitin-modified proteome identifies novel host determinants of Kaposi’s sarcoma herpesvirus lytic rea (as deposited) · PXD046571
  • Arginine methylation during transcriptional arrest (as deposited) · PXD000559
  • BRCA1-dependent ubiquitination and phosphorylation regulates signaling events in high-grade serous ovarian cancer tissue (as deposited) · PXD020271
  • Characterization of Arginine Methylation in Cancer Cell using LC-MS/MS (as deposited) · PXD039441
  • DNA-PKcs kinase activity stabilizes the transcription factor Egr1 in activated immune cells (as deposited) · PXD026352
  • Decrypting drug actions and protein modifications by dose- and time-resolved chemical proteomics (as deposited) · PXD037285
  • Definition of aberrant MYB CBP/P300 complex in AML (as deposited) · PXD019708
  • High-dose oncogenic PIK3CA drives constitutive cellular stemness through increased NODAL/TGFb signaling (as deposited) · PXD014719
  • Human Arginine Methylome - Proteome-wide analysis of arginine monomethylation reveals widespread occurrence in human cel (as deposited) · PXD003700
  • IPX001804000 (as deposited) · IPX001804000
  • Identification of MRCKA as an integral component of ovarian cancer signaling and a therapeutic target (as deposited) · PXD015782
  • Improved functional annotation of posttranslationally modified proteins (as deposited) · PXD002800
  • InstaNovo-P FGFR2 phosphoproteomics (as deposited) · InstaDeepAI/PXD062859, PXD062859
  • Integrated lysine acetylation stoichiometry and proteomics analysis in human cells (as deposited) · PXD005903
  • Integrated proteomic analysis of Tumor Necrosis Factor α and Interleukin 1 β-induced endothelial inflammation (as deposited) · PXD009174
  • Integrative phosphoproteomic analysis reveal hemostatic-endothelial signaling interplay (as deposited) · PXD052627
  • Lztr1 loss leads to Noonan syndrome-like vascular defects by dysregulating vesicular trafficking (as deposited) · PXD011926
  • Mapping Ubiquitination Sites in Alzheimer’s Disease (as deposited) · PXD009199
  • Mutations in TRAF7 drive meningioma development by dysregulating proteostasis of the RAS-like GTPases (as deposited) · PXD021188
  • Nine-species benchmark (original (DeepNovo, 2017)) · MSV000081382, PXD003868 (provenance), PXD004325 (provenance), PXD004424 (provenance), PXD004467 (provenance), PXD004536 (provenance), PXD004565 (provenance), PXD004947 (provenance), PXD004948 (provenance), PXD005025 (provenance)
  • Nine-species benchmark (revised (main)) · 10.5281/zenodo.12926326, Noble-Lab/multi-species-benchmark, MSV000090982, 10.5281/zenodo.13685813
  • PRMT1 controls the Senescence Associated Secretory Phenotype in Replication Stress Response (as deposited) · PXD014799
  • Phosphoproteomic-based kinase profiling early in influenza virus infection (as deposited) · PXD009999
  • ProMetheus: a database of hmSILAC-validated protein methylation sites (as deposited) · PXD027949
  • Profiling of Proteome and Ubiquitome Changesin in endothelial cells in response to shear stress (as deposited) · PXD024309
  • Proteomics Profiling of Arginine Methylation Defines PRMT5 Substarate Specificity (as deposited) · PXD009070
  • Quantitative Analysis of Lysine Acetylation in A549 Cell Line (as deposited) · PXD023468
  • Quantitative phosphoproteomic analysis of acquired drug resistance to pazopanib and dasatinib (as deposited) · PXD005536
  • TBK1 interacts with tau and enhances neurodegeneration in tauopathy (as deposited) · PXD025301
  • Therapeutic targeting of RNA splicing catalysis through inhibition of protein arginine methylation (as deposited) · PXD012007
  • Time-resolved analysis reveals rapid dynamics and broad scope of the CBP/p300 acetylome (as deposited) · PXD005252

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