A modification-centric assessment tool for the performance of chemoproteomic probes

  • Nat Chem Biol. 2022 Aug;18(8):904-912. doi: 10.1038/s41589-022-01074-8.
Ji-Xiang He  #  1  2  3  4  5  6 ,  Zheng-Cong Fei  #  7  8  9 ,  Ling Fu  3  4  5  6 ,  Cai-Ping Tian  3  4  5  6 ,  Fu-Chu He  3  4  5  6 ,  Hao Chi  10  11  12 ,  Jing Yang  13  14  15  16
Affiliations
  • 1. The Joint Graduate Program with National Center for Protein Sciences, Hebei University, Baoding, China.
  • 2. College of Chemistry & Environmental Science, Hebei University, Baoding, China.
  • 3. State Key Laboratory of Proteomics, Beijing, China.
  • 4. Beijing Proteome Research Center, Beijing, China.
  • 5. National Center for Protein Sciences, Beijing, China.
  • 6. Beijing Institute of Lifeomics, Beijing, China.
  • 7. Key Laboratory of Intelligent Information Processing of Chinese Academy of Sciences, Beijing, China.
  • 8. Institute of Computing Technology, Chinese Academy of Sciences, Beijing, China.
  • 9. University of Chinese Academy of Sciences, Beijing, China.
  • 10. Key Laboratory of Intelligent Information Processing of Chinese Academy of Sciences, Beijing, China. [email protected].
  • 11. Institute of Computing Technology, Chinese Academy of Sciences, Beijing, China. [email protected].
  • 12. University of Chinese Academy of Sciences, Beijing, China. [email protected].
  • 13. State Key Laboratory of Proteomics, Beijing, China. [email protected].
  • 14. Beijing Proteome Research Center, Beijing, China. [email protected].
  • 15. National Center for Protein Sciences, Beijing, China. [email protected].
  • 16. Beijing Institute of Lifeomics, Beijing, China. [email protected].
  • # Contributed equally.
PMID: 35864333 DOI: 10.1038/s41589-022-01074-8
Abstract

Chemoproteomics has emerged as a key technology to expand the functional space in complex proteomes for probing fundamental biology and for discovering new small-molecule-based therapies. Here we report a modification-centric computational tool termed pChem to provide a streamlined pipeline for unbiased performance assessment of chemoproteomic probes. The pipeline starts with an experimental setting for isotopically coding probe-derived modifications that can be automatically recognized by pChem, with masses accurately calculated and sites precisely localized. pChem exports on-demand reports by scoring the profiling efficiency, modification homogeneity and proteome-wide residue selectivity of a tested probe. The performance and robustness of pChem were benchmarked by applying it to eighteen bioorthogonal probes. These analyses reveal that the formation of unexpected probe-derived modifications can be driven by endogenous reactive metabolites (for example, bioactive aldehydes and glutathione). pChem is a powerful and user-friendly tool that aims to facilitate the development of probes for the ever-growing field of chemoproteomics.

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