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Cooperativity in protein-folding kinetics

K A Dill1, K M Fiebig, H S Chan

  • 1Department of Pharmaceutical Chemistry, University of California, San Francisco 94143-1204.

Proceedings of the National Academy of Sciences of the United States of America
|March 1, 1993
PubMed
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The hydrophobic zipper (HZ) hypothesis proposes proteins rapidly find their native state via sequential hydrophobic contacts. This mechanism explains protein folding pathways without exhaustive searching, forming compact intermediate states.

Area of Science:

  • Protein folding and biophysics
  • Computational biology and structural bioinformatics

Background:

  • Proteins must efficiently navigate vast conformational landscapes to reach their native state.
  • Existing models like helix-coil cooperativity do not fully explain the speed and efficiency of protein folding.

Purpose of the Study:

  • To propose and validate the hydrophobic zipper (HZ) hypothesis for protein folding.
  • To elucidate the role of nonlocal hydrophobic interactions in driving protein collapse and structure formation.

Main Methods:

  • Analysis of hydrophobic contact topology in the 1992 Protein Data Bank.
  • Computational simulation of HZ pathways for crambin and bovine pancreatic trypsin inhibitor sequences.

Main Results:

Related Experiment Videos

  • Hydrophobic contacts exhibit 'topological localness' consistent with the HZ hypothesis.
  • HZ pathways were rapidly identified computationally for model protein sequences.
  • Simulated protein configurations achieved near-global minimum energy states (within 3 kcal/mol).
  • Conclusions:

    • The hydrophobic zipper hypothesis provides a viable mechanism for rapid protein folding.
    • Nonlocal hydrophobic interactions drive heteropolymer collapse cooperativity, leading to concurrent secondary structure and hydrophobic core formation.
    • This model explains how proteins achieve optimal structures without exhaustive conformational searches.