Polymer scaling laws of unfolded and intrinsically disordered proteins quantified with single-molecule spectroscopy

Hagen Hofmann, Andrea Soranno, Alessandro Borgia, Klaus Gast, Daniel Nettels, Benjamin Schuler

Research output: Contribution to journalArticlepeer-review

256 Scopus citations


The dimensions of unfolded and intrinsically disordered proteins are highly dependent on their amino acid composition and solution conditions, especially salt and denaturant concentration. However, the quantitative implications of this behavior have remained unclear, largely because the effective theta-state, the central reference point for the underlying polymer collapse transition, has eluded experimental determination. Here, we used single-molecule fluorescence spectroscopy and two-focus correlation spectroscopy to determine the theta points for six different proteins. While the scaling exponents of all proteins converge to 0.62 ± 0.03 at high denaturant concentrations, as expected for a polymer in good solvent, the scaling regime in water strongly depends on sequence composition. The resulting average scaling exponent of 0.46 ± 0.05 for the four foldable protein sequences in our study suggests that the aqueous cellular milieu is close to effective theta conditions for unfolded proteins. In contrast, two intrinsically disordered proteins do not reach the Θ-point under any of our solvent conditions, which may reflect the optimization of their expanded state for the interactions with cellular partners. Sequence analyses based on our results imply that foldable sequences with more compact unfolded states are a more recent result of protein evolution.

Original languageEnglish
Pages (from-to)16155-16160
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number40
StatePublished - Oct 2 2012


  • Coil-globule transition
  • Polymer theory
  • Protein folding
  • Single-molecule FRET


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