Tailoring protein nanomechanics with chemical reactivity

Amy E M Beedle, Marc Mora, Steven Lynham, Guillaume Stirnemann, Sergi Garcia-Manyes

Research output: Contribution to journalArticlepeer-review

23 Citations (Scopus)
172 Downloads (Pure)


The nanomechanical properties of elastomeric proteins determine the elasticity of a variety of tissues. A widespread natural tactic to regulate protein extensibility lies in the presence of covalent disulfide bonds, which significantly enhance protein stiffness. The prevalent in vivo strategy to form disulfide bonds requires the presence of dedicated enzymes. Here we propose an alternative chemical route to promote non-enzymatic oxidative protein folding via disulfide isomerization based on naturally occurring small molecules. Using single-molecule force-clamp spectroscopy, supported by DFT calculations and mass spectrometry measurements, we demonstrate that subtle changes in the chemical structure of a transient mixed-disulfide intermediate adduct between a protein cysteine and an attacking low molecular-weight thiol have a dramatic effect on the protein's mechanical stability. This approach provides a general tool to rationalize the dynamics of S-thiolation and its role in modulating protein nanomechanics, offering molecular insights on how chemical reactivity regulates protein elasticity.

Original languageEnglish
Article number15658
Pages (from-to)1-11
JournalNature Communications
Issue number1
Early online date6 Jun 2017
Publication statusPublished - 6 Jun 2017


  • Cysteine/chemistry
  • Disulfides/chemistry
  • Escherichia coli/metabolism
  • Humans
  • Hydrogen-Ion Concentration
  • Mass Spectrometry
  • Models, Molecular
  • Mutation
  • Oxygen/chemistry
  • Protein Conformation
  • Protein Engineering/methods
  • Protein Folding
  • Protein Stability
  • Proteins/chemistry
  • Spectrophotometry
  • Spectrophotometry, Ultraviolet
  • Sulfhydryl Compounds
  • Thermodynamics


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