Learning from tandem mass spectra at scale with a self-supervised foundation model for proteomics

preprint · bioRxiv · 2026

preprint · bioRxiv · 2026. Mechiel Nieuwoudt et al. Mass spectrometry-based proteomics increasingly relies on machine learning, yet existing models are trained…
Date 2026-09-03
Type preprint
Venue bioRxiv
Publisher Cold Spring Harbor Laboratory
Contribution algorithm
DOI 10.64898/2026.09.03.747733
Citations (OpenAlex) 0

Abstract

Mass spectrometry-based proteomics increasingly relies on machine learning, yet existing models are trained for defined supervised tasks such as peptide identification, de novo sequencing or fragment intensity prediction, limiting transfer across datasets, instruments and acquisition methods. Here we present InstaNovo-FM, a self-supervised foundation model for bottom-up proteomics trained to reconstruct masked regions of tandem mass spectra. We assemble a diverse training corpus spanning 1.47 billion MS/MS spectra and 184.6 million high-confidence annotations. We train an encoder-only transformer on the annotated tier using a physics-aware masked reconstruction objective. We demonstrate that the InstaNovo-FM embeddings encode fundamental experimental and biological properties, including fragmentation method, sequence properties and post-translational modifications, without requiring peptide labels. Furthermore, this foundation model directly enables diverse downstream applications, including de novo peptide sequencing, database-free identification and analytical run classification. InstaNovo-FM establishes a unified representation space for peptide fragmentation spectra, enabling robust transferability across the proteomics ecosystem.

Authors

  1. Mechiel Nieuwoudt · InstaDeep Ltd
  2. Marco Reverenna · Technical University of Denmark
  3. Divanisha Patel · InstaDeep Ltd
  4. Rachel Catzel · InstaDeep Ltd
  5. Isaac H.J. Houngue · African Institute for Mathematical Sciences, InstaDeep Ltd
  6. Jemma Daniel · InstaDeep Ltd
  7. Kevin Eloff · InstaDeep Ltd
  8. Alberto Santos · Technical University of Denmark
  9. Nicolas Lopez Carranza · InstaDeep Ltd
  10. Timothy P. Jenkins · Technical University of Denmark
  11. Jeroen Van Goey · InstaDeep Ltd
  12. Konstantinos Kalogeropoulos · Delft University of Technology, Kavli Institute of Nanoscience, Technical University of Denmark

Methods and tools

  • InstaNovo-FM: Self-supervised foundation model for bottom-up proteomics: an encoder-only transformer trained to reconstruct masked regions of tandem mass spectra under a physics-aware objective, over a corpus of 1.47 billion MS/MS spectra with 184.6 million high-confidence annotations. The embeddings capture fragmentation method, sequence properties and post-translational modifications without peptide labels, and support de novo sequencing, database-free identification and analytical run classification as downstream tasks.

Data used

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  • Benchmarking of single cell proteomics data analysis workflows (as deposited) · PXD046211
  • Candida auris proteomic profiling (as deposited) · PXD046911
  • Cervical Cancer Tissue Immunopeptidomics (as deposited) · PXD046182
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  • Confetti: A Multi-protease Map of the HeLa Proteome for Comprehensive Proteomics (as deposited) · PXD000900
  • Correction To - Confetti: A Multi-protease Map of the HeLa Proteome for Comprehensive Proteomics (as deposited) · PXD001258
  • DCAF1-based PROTACs with activity against clinically validated targets overcoming intrinsic- and acquired-degrader resis (as deposited) · PXD046286
  • DIA-based phosphoproteomics identifies early phosphorylation events in response to EGTA and mannitol in Arabidopsis (as deposited) · PXD046802
  • Deep Human Proteome Sequencing Enables Global Detection of Mutations and Alternative Splicing (as deposited) · PXD024364
  • Determinants of the cellular immunopeptidome -cellular peptidome (as deposited) · PXD009935
  • Differential interaction proteomics and phosphoproteomics of STK17B on an Oribtrap Astral, Nikiforov (as deposited) · PXD068040
  • Effect of an immune challenge and feed supplements on broiler chicken individual breast muscle protein synthesis (as deposited) · PXD044325
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  • Expanding proteome coverage with CHarge Ordered Parallel Ion aNalysis (CHOPIN) combined with broad specificity proteolys (as deposited) · PXD003977
  • Expanding the Landscape of Aging via Orbitrap Astral Mass Spectrometry and Tandem Mass Tag (TMT) Integration (as deposited) · PXD058160
  • Generation of ENSEMBL-based proteogenomics databases boost the identification of novel peptides (as deposited) · PXD029360
  • Global, site-resolved analysis of ubiquitylation occupancy and turnover rate reveals systems properties (as deposited) · PXD037009
  • Glycoproteomic analysis of Fut8 knock out/wild type mouse brain, Human IgG and Human Serum. (as deposited) · PXD035158
  • HeLa proteome of 12,250 protein-coding genes (as deposited) · PXD004452
  • High-throughput MS-based immunopeptidomics (as deposited) · PXD006939
  • High-throughput proteomics of the 26 medically most important elapids and vipers from sub-Saharan Africa (as deposited) · PXD036161
  • Human breast adipose tissue extracellular vesicles (as deposited) · PXD045471
  • Human serum glycoproteome - Glyco-Decipher (as deposited) · PXD031025
  • Immunopeptidomics of colorectal cancer organoids (as deposited) · PXD014017
  • Immunopeptidomics-based identification of naturally presented non-canonical circRNA-derived peptides (as deposited) · PXD043989
  • InstaNovo enables diffusion-powered de novo peptide identification in large scale proteomics experiments (as deposited) · PXD044934, 10.6084/m9.figshare.24173889
  • InstaNovo-P Astral (yeast new1 knock-out) (as deposited) · InstaDeepAI/PXD055983, PXD055983
  • Integrating Alternative Fragmentation Techniques into Standard LC-MS Workflows Using a Single Deep Learning Model Enhanc (as deposited) · PXD065289
  • Large-scale proteomics analysis of five brain regions from Parkinson’s disease patients with a GBA1 mutation (as deposited) · PXD047134
  • Longitudinal evaluation of biomarkers in wound fluids of venous leg ulcers treated with a protease-modulating wound dressing (as deposited) · PXD025748
  • Machine Learning Based Classification of Diffuse Large B-cell Lymphoma Patients by their Protein Expression Profiles (as deposited) · PXD002052
  • Mapping the substrate landscape of protein phosphatase 2A catalytic subunit PPP2CA (as deposited) · PXD045779
  • Mass spectrometry based draft of the human proteome (as deposited) · PXD000865
  • Maximizing glycoproteomics identification depth in complex mixtures on the timsTOF Pro platform (as deposited) · PXD047898
  • Mycobacterium tuberculosis Quantitative proteomics (as deposited) · PXD068926
  • NeoDisc: A neoantigen discovery pipeline for the development of personalized cancer immunotherapy (as deposited) · PXD047641
  • Nine-species benchmark (version not stated)
  • Optimization of Experimental Parameters in Data-Independent Mass Spectrometry Significantly Increases Depth and Reproduc (as deposited) · PXD005573
  • PXD057992 (as deposited) · PXD057992
  • Precision N-glycoproteomics of murine peritoneal macrophage (as deposited) · PXD026629
  • Precision mapping of glycosite-specific glycans reveals distinctive N-glycosylation on human spermatozoa (as deposited) · PXD026649
  • Proteins of anti-sigma70 and anti-RNAP immunoprecipitates in bacteria (as deposited) · PXD047705
  • Proteome profiling of cerebrospinal fluid and machine learning reveal biomarkers of two forms of Alzheimer’s disease cha (as deposited) · PXD063058
  • Proteome-wide identification of cysteine S-sulfenylation in response to low temperature and low-humidity stress in Dendr (as deposited) · PXD074422
  • ProteomeTools (21-PTM subset) · InstaDeepAI/PXD009449, PXD009449
  • ProteomeTools (Parts I-III) · PXD004732, PXD010595, PXD021013
  • ProteomeTools Part VI - Citrullinated peptides (as deposited) · PXD056559
  • Proteomic analysis of innate immune responses in Polg D257A macrophages challenged with Pseudomonas aeruginosa (as deposited) · PXD062877
  • Proteomic data of the Trypanosoma cruzi RNA-binding protein UBP1 induction and knockdown in insect-dwelling epimastigote (as deposited) · PXD047761
  • Pure and mixed crude extracts of Thauera aromatica K172 and Pseudomonas putida KT2440 for benchmarking GroEL-proteotypin (as deposited) · PXD046460
  • Quantitative differences in rumen epithelium proteins in lambs fed wheat, perennial wheat or perennial wheat plus lucern (as deposited) · PXD044135
  • Quantitative profiling of proteome extracted from zebrafish embryos exposed to different concentrations of the fungicide (as deposited) · PXD045650
  • Quantitative proteomic profiling of ruptured and unruptured brain arteriovenous malformations (as deposited) · PXD074343
  • Rapid and site-specific deep phosphoproteome profiling by data-independent acquisition (DIA) without the need for spectr (as deposited) · PXD014525
  • Re-analysis of glycoproteomics data with Glyco-Decipher (as deposited) · PXD031032
  • Reconstruction of Metabolic Pathways, Protein Expression, and Homeostasis Machineries across Maize Bundle Sheath and Mes (as deposited) · PXD044303
  • SARS-CoV-2 Envelope TurboID LFQ using internal tagging (as deposited) · PXD045299
  • Site- and structure-specific glycosylation signatures of bovine, caprine, porcine and human milk-derived extracellular v (as deposited) · PXD044641
  • Structural Interpretation of Glycosite-specific N-Glycans Using Tandem Mass Spectrometry (as deposited) · PXD025859
  • Structure and mechanism of the Zorya anti-phage defense system (as deposited) · PXD047450
  • Systematic HLA Epitope Ranking Pan Algorithm (SHERPA) (as deposited) · PXD023064
  • The Proteome Landscape of the Kingdoms of Life (as deposited) · PXD014877, PXD019483
  • The Secretome of Macrophages Has a Differential Impact on Spinal Cord Injury Recovery According to the Polarization Prot (as deposited) · PXD048453
  • The natural diversity of the yeast proteome links aneuploidy tolerance to protein turnover (as deposited) · PXD048219
  • The one hour human proteome: Orbitrap Astral Mass Spectrometer (as deposited) · PXD049028
  • The phosphorylation landscape of infection-related development by the rice blast fungus (as deposited) · PXD044830
  • The type 1 diabetes (T1D) susceptibility gene PGM1 disrupts metabolic homeostasis in pancreatic beta cell in response to (as deposited) · PXD074720
  • Thermal proteome profiling of sponge whole-body movement (as deposited) · PXD044169
  • Ubiquitinome of Plasmodium yoelii lines NSS and NSR (as deposited) · PXD047782
  • Ubiquiton – an inducible, linkage-specific polyubiquitylation tool (as deposited) · PXD045662
  • Ultra-fast label-free quantification and comprehensive proteome coverage with narrow-window data-independent acquisition (as deposited) · PXD046453
  • VAP spatially stabilizes dendritic mitochondria to locally support synaptic plasticity (as deposited) · PXD047226
  • WELFARE OF RAINBOW TROUT AT SLAUGHTER: INTEGRATING BEHAVIOURAL, PHYSIOLOGICAL, PROTEOMIC AND QUALITY INDICATORS (as deposited) · PXD044301
  • iTRAQ-based proteomics reveals potential markers and treatment pathways for acute Achilles tendon rupture (as deposited) · PXD046451
  • timsTOF HT improves protein identification and quantitative reproducibility for deep unbiased plasma protein biomarker d (as deposited) · PXD047839

Cites (17)

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