Enhancing protein dynamics analysis with hydrophilic polyethylene glycol cross-linkers.

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  • Additional Information
    • Source:
      Publisher: Oxford University Press Country of Publication: England NLM ID: 100912837 Publication Model: Print Cited Medium: Internet ISSN: 1477-4054 (Electronic) Linking ISSN: 14675463 NLM ISO Abbreviation: Brief Bioinform Subsets: MEDLINE
    • Publication Information:
      Publication: Oxford : Oxford University Press
      Original Publication: London ; Birmingham, AL : H. Stewart Publications, [2000-
    • Subject Terms:
      Polyethylene Glycols*/chemistry ; Proteins*/chemistry; Mass Spectrometry ; Protein Conformation ; Molecular Dynamics Simulation
    • Abstract:
      Cross-linkers play a critical role in capturing protein dynamics in chemical cross-linking mass spectrometry techniques. Various types of cross-linkers with different backbone features are widely used in the study of proteins. However, it is still not clear how the cross-linkers' backbone affect their own structure and their interactions with proteins. In this study, we systematically characterized and compared methylene backbone and polyethylene glycol (PEG) backbone cross-linkers in terms of capturing protein structure and dynamics. The results indicate the cross-linker with PEG backbone have a better ability to capture the inter-domain dynamics of calmodulin, adenylate kinase, maltodextrin binding protein and dual-specificity protein phosphatase. We further conducted quantum chemical calculations and all-atom molecular dynamics simulations to analyze thermodynamic and kinetic properties of PEG backbone and methylene backbone cross-linkers. Solution nuclear magnetic resonance was employed to validate the interaction interface between proteins and cross-linkers. Our findings suggest that the polarity distribution of PEG backbone enhances the accessibility of the cross-linker to the protein surface, facilitating the capture of sites located in dynamic regions. By comprehensively benchmarking with disuccinimidyl suberate (DSS)/bis-sulfosuccinimidyl-suberate(BS3), bis-succinimidyl-(PEG)2 revealed superior advantages in protein dynamic conformation analysis in vitro and in vivo, enabling the capture of a greater number of cross-linking sites and better modeling of protein dynamics. Furthermore, our study provides valuable guidance for the development and application of PEG backbone cross-linkers.
      (© The Author(s) 2024. Published by Oxford University Press.)
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    • Grant Information:
      31971155 National Natural Science Foundation; 2020329 Youth Innovation Promotion Association of the Chinese Academy of Sciences
    • Contributed Indexing:
      Keywords: MD simulations; NMR; cross-linking; poly ethylene glycol (PEG); protein dynamics
    • Accession Number:
      3WJQ0SDW1A (Polyethylene Glycols)
      0 (Proteins)
    • Publication Date:
      Date Created: 20240212 Date Completed: 20240214 Latest Revision: 20240214
    • Publication Date:
      20240214
    • Accession Number:
      PMC10859660
    • Accession Number:
      10.1093/bib/bbae026
    • Accession Number:
      38343324