Eliminating a Protein Folding Intermediate by Tuning a Local Hydrophobic Contact

Khatuna Kachlishvili, Kapil Dave, Martin Gruebele, Harold A. Scheraga, Gia G. Maisuradze

Research output: Contribution to journalArticlepeer-review


Intermediate states in protein folding may slow folding, and sometimes can provide a starting point for aggregation. Recently, the FBP28 WW domain of the formin-binding protein was used as a model for a computational study of the origin and prevention of intermediate-state formation, and local hydrophobic interactions of Leu26 were implicated. Here, we combine new simulations over a broad temperature range with experimental temperature-jump data to study this site in more detail. We replace Leu26 by Asp26 or Trp26 to alter the folding scenario from three-state folding toward two-state or downhill folding at temperatures below the melting point, whereas the wild type shows two-state behavior only near its melting temperature. We offer an explanation of this behavior mainly in terms of principles of hydrophobic interactions.

Original languageEnglish (US)
Pages (from-to)3276-3284
Number of pages9
JournalJournal of Physical Chemistry B
Issue number15
StatePublished - Apr 20 2017

ASJC Scopus subject areas

  • Physical and Theoretical Chemistry
  • Surfaces, Coatings and Films
  • Materials Chemistry


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