A natural missing link between activated and downhill protein folding scenarios

Feng Liu, Caroline Maynard, Gregory Scott, Artem Melnykov, Kathleen B. Hall, Martin Gruebele

Research output: Contribution to journalArticlepeer-review

4 Scopus citations


We propose protein PTB14W as a good candidate for engineering into a downhill folder. PTB14W has a probe-dependent thermal unfolding curve and sub-millisecond T-jump relaxation kinetics on more than one time scale. Its refolding rate in denaturant is a non-linear function of denaturant concentration (curved chevron plot). Yet at high denaturant concentration its unfolding is probe-independent, and the folding kinetics can be fitted to a single exponential decay. The domain appears to fold via a mechanism between downhill folding and activated folding over several small barriers, and when denaturant is added, one of these barriers greatly increases and simplifies the observed folding to apparent two-state kinetics. We predict the simplest free energy function consistent with the thermal denaturation and kinetics experiments by using the singular value Smoluchowski dynamics (SVSD) model. PTB14W is a natural 'missing link' between downhill and activated folding. We suggest mutations that could move the protein into the downhill folding limit.

Original languageEnglish
Pages (from-to)3542-3549
Number of pages8
JournalPhysical Chemistry Chemical Physics
Issue number14
StatePublished - 2010


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