TY - JOUR
T1 - Eliminating a Protein Folding Intermediate by Tuning a Local Hydrophobic Contact
AU - Kachlishvili, Khatuna
AU - Dave, Kapil
AU - Gruebele, Martin
AU - Scheraga, Harold A.
AU - Maisuradze, Gia G.
N1 - Funding Information:
The theoretical research was conducted by using the resources of (i) our 588-processor Beowulf cluster at the Baker Laboratory of Chemistry and Chemical Biology, Cornell University, and (ii) the National Science Foundation Terascale Computing System at the Pittsburgh Supercomputer Center. The computational work was supported by grants from the National Institutes of Health (GM-14312) and the National Science Foundation (MCB10-19767). This work was also supported by a grant from the National Institutes of Health, 2R01 GM093318, for the experimental work at the University of Illinois Urbana-Champaign (K.D. and M.G.).
Publisher Copyright:
© 2016 American Chemical Society.
PY - 2017/4/20
Y1 - 2017/4/20
N2 - 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.
AB - 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.
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U2 - 10.1021/acs.jpcb.6b07250
DO - 10.1021/acs.jpcb.6b07250
M3 - Article
C2 - 27584585
AN - SCOPUS:85020042781
VL - 121
SP - 3276
EP - 3284
JO - Journal of Physical Chemistry B
JF - Journal of Physical Chemistry B
SN - 1520-6106
IS - 15
ER -