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Modulation of frustration in folding by sequence permutation.

R Paul Nobrega1, Karunesh Arora2, Sagar V Kathuria1

  • 1Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01605;

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Summary

Protein folding frustration, a key factor in aggregation, was studied in bacterial CheY protein. Altering sequence connectivity revealed that aliphatic-rich sequences and chain entropy significantly influence early folding events and kinetic traps.

Keywords:
CF-SAXSCheY permutantsGō modelsprotein-folding intermediates

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Area of Science:

  • Protein folding dynamics
  • Biophysics
  • Molecular biology

Background:

  • Protein folding involves navigating a complex energy landscape with potential traps.
  • Frustration in protein folding can lead to off-pathway intermediates and aggregation.
  • The sequence determinants of frustration in globular proteins remain poorly understood.

Purpose of the Study:

  • To investigate the relationship between sequence determinants and frustration in protein folding.
  • To elucidate the roles of subdomains and aliphatic side chains in the frustration of CheY protein.
  • To understand how altered sequence connectivity affects protein folding intermediates and kinetics.

Main Methods:

  • Circular permutation of the chemotaxis response regulator Y (CheY) protein sequence.
  • Analysis of protein stability and buried surface area of folding intermediates.
  • Comparison with small-angle X-ray scattering (SAXS) experiments and molecular simulations.

Main Results:

  • Altering sequence connectivity modulated the stability and buried surface area of CheY intermediates.
  • More stable intermediates correlated with accelerated formation of compact, on-pathway species.
  • Both subdomain interactions and aliphatic-rich sequences (ILV clusters) contribute to frustration.

Conclusions:

  • Chain connectivity significantly impacts frustration and kinetic traps in CheY folding.
  • The ILV cluster model better explains modulated intermediate structures and stabilities.
  • An intact N-terminal domain is crucial for accessing the native conformation, highlighting the interplay of sequence and structural elements.