Discrete Diffusion with Physical Mass Constraints for De Novo Peptide Sequencing

An Zeyu, Wanyu Lin
Proceedings of the 43rd International Conference on Machine Learning, PMLR 306:153845-153861, 2026.

Abstract

$\textit{De novo}$ peptide sequencing is a pivotal technique that directly reconstructs amino acid sequences from tandem mass spectrometry (MS/MS) data; it enables the identification of novel proteins and variants absent from reference databases. Previous methods are typically based on autoregressive (AR) decoding or one-shot generation. The AR-based methods conflict with the bidirectional and globally constrained nature of MS/MS evidence and inevitably accumulate errors, while one-shot generation does not explicitly enforce physical constraints, failing to produce chemically valid and reliable peptides in a single pass. Accurate sequencing necessitates reasoning over the entire peptide simultaneously, enabling iterative self-correction under global constraints. To this end, we introduce $\textbf{PhysNovo}$, a novel paradigm that harnesses discrete diffusion to enable simultaneous global reasoning and iterative refinement. Specifically, PhysNovo reformulates sequencing as a $\textbf{phys}$ically mass-constrained reasoning process by embedding a knapsack-based feasibility kernel to enforce exact precursor mass consistency. By conditioning the diffusion process on global spectral context, PhysNovo supports abductive reasoning where bidirectional evidence is exploited to iteratively resolve local inconsistencies and ensure physically valid predictions. PhysNovo achieves state-of-the-art performance, exceeding baselines by over 2% in precision, with larger gains on out-of-distribution data. The source code is publicly available at https://github.com/WanyuGroup/ICML2026_PhysNovo.

Cite this Paper

BibTeX
@InProceedings{pmlr-v306-zeyu26a, title = {Discrete Diffusion with Physical Mass Constraints for De Novo Peptide Sequencing}, author = {Zeyu, An and Lin, Wanyu}, booktitle = {Proceedings of the 43rd International Conference on Machine Learning}, pages = {153845--153861}, year = {2026}, editor = {Zhang, Tong and Dudik, Miroslav and Jaggi, Martin and Agarwal, Alekh and Li, Sharon and Schuurmans, Dale and Zhu, Jerry and Berkenkamp, Felix and Dong, Hanze and Bietti, Alberto}, volume = {306}, series = {Proceedings of Machine Learning Research}, month = {06--11 Jul}, publisher = {PMLR}, pdf = {https://raw.githubusercontent.com/mlresearch/v306/main/assets/zeyu26a/zeyu26a.pdf}, url = {https://proceedings.mlr.press/v306/zeyu26a.html}, abstract = {$\textit{De novo}$ peptide sequencing is a pivotal technique that directly reconstructs amino acid sequences from tandem mass spectrometry (MS/MS) data; it enables the identification of novel proteins and variants absent from reference databases. Previous methods are typically based on autoregressive (AR) decoding or one-shot generation. The AR-based methods conflict with the bidirectional and globally constrained nature of MS/MS evidence and inevitably accumulate errors, while one-shot generation does not explicitly enforce physical constraints, failing to produce chemically valid and reliable peptides in a single pass. Accurate sequencing necessitates reasoning over the entire peptide simultaneously, enabling iterative self-correction under global constraints. To this end, we introduce $\textbf{PhysNovo}$, a novel paradigm that harnesses discrete diffusion to enable simultaneous global reasoning and iterative refinement. Specifically, PhysNovo reformulates sequencing as a $\textbf{phys}$ically mass-constrained reasoning process by embedding a knapsack-based feasibility kernel to enforce exact precursor mass consistency. By conditioning the diffusion process on global spectral context, PhysNovo supports abductive reasoning where bidirectional evidence is exploited to iteratively resolve local inconsistencies and ensure physically valid predictions. PhysNovo achieves state-of-the-art performance, exceeding baselines by over 2% in precision, with larger gains on out-of-distribution data. The source code is publicly available at https://github.com/WanyuGroup/ICML2026_PhysNovo.} }
Endnote
%0 Conference Paper %T Discrete Diffusion with Physical Mass Constraints for De Novo Peptide Sequencing %A An Zeyu %A Wanyu Lin %B Proceedings of the 43rd International Conference on Machine Learning %C Proceedings of Machine Learning Research %D 2026 %E Tong Zhang %E Miroslav Dudik %E Martin Jaggi %E Alekh Agarwal %E Sharon Li %E Dale Schuurmans %E Jerry Zhu %E Felix Berkenkamp %E Hanze Dong %E Alberto Bietti %F pmlr-v306-zeyu26a %I PMLR %P 153845--153861 %U https://proceedings.mlr.press/v306/zeyu26a.html %V 306 %X $\textit{De novo}$ peptide sequencing is a pivotal technique that directly reconstructs amino acid sequences from tandem mass spectrometry (MS/MS) data; it enables the identification of novel proteins and variants absent from reference databases. Previous methods are typically based on autoregressive (AR) decoding or one-shot generation. The AR-based methods conflict with the bidirectional and globally constrained nature of MS/MS evidence and inevitably accumulate errors, while one-shot generation does not explicitly enforce physical constraints, failing to produce chemically valid and reliable peptides in a single pass. Accurate sequencing necessitates reasoning over the entire peptide simultaneously, enabling iterative self-correction under global constraints. To this end, we introduce $\textbf{PhysNovo}$, a novel paradigm that harnesses discrete diffusion to enable simultaneous global reasoning and iterative refinement. Specifically, PhysNovo reformulates sequencing as a $\textbf{phys}$ically mass-constrained reasoning process by embedding a knapsack-based feasibility kernel to enforce exact precursor mass consistency. By conditioning the diffusion process on global spectral context, PhysNovo supports abductive reasoning where bidirectional evidence is exploited to iteratively resolve local inconsistencies and ensure physically valid predictions. PhysNovo achieves state-of-the-art performance, exceeding baselines by over 2% in precision, with larger gains on out-of-distribution data. The source code is publicly available at https://github.com/WanyuGroup/ICML2026_PhysNovo.
APA
Zeyu, A. & Lin, W.. (2026). Discrete Diffusion with Physical Mass Constraints for De Novo Peptide Sequencing. Proceedings of the 43rd International Conference on Machine Learning, in Proceedings of Machine Learning Research 306:153845-153861 Available from https://proceedings.mlr.press/v306/zeyu26a.html.

Related Material