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Related Experiment Videos

Large-scale context in protein folding: villin headpiece.

Ariel Fernández1, Min-yi Shen, Andrés Colubri

  • 1Institute for Biophysical Dynamics, University of Chicago, 920 East 58th Street, Chicago, Illinois 60637, USA. ariel@uchicago.edu

Biochemistry
|January 22, 2003
PubMed
Summary

Villin headpiece folding is guided by unexpected hydrophobic residue correlations that protect hydrogen bonds. These three-body interactions promote C-terminal helix formation, overcoming local sequence disfavors.

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Area of Science:

  • Protein folding dynamics
  • Computational biophysics
  • Molecular biology

Background:

  • The villin headpiece folds into three alpha-helical regions in vitro.
  • Local residue propensities disfavor C-terminal helix formation due to hydrophobic/polar mismatches.
  • AGADIR criterion suggests the N-terminal helix is also unfavored.

Purpose of the Study:

  • To investigate the folding mechanism of the villin headpiece.
  • To understand the role of residue correlations in protein folding.
  • To identify key interactions guiding helix formation.

Main Methods:

  • Coarse-grained ab initio simulations
  • All-atom simulations with implicit solvent model
  • Comparison with explicit solvent simulations

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Main Results:

  • Three-body correlations involving hydrophobic residues were identified.
  • These correlations protect amide-carbonyl hydrogen bonds from water.
  • This protection induces C-terminal helix growth and guides folding.
  • Simulations accurately reproduced experimental results.

Conclusions:

  • Hydrophobic residue correlations play a crucial role in villin headpiece folding.
  • A large-scale, many-body context influences protein folding dynamics.
  • Experimental mutations outside the hydrophobic core can probe these folding mechanisms.