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Related Experiment Videos

Filling small, empty protein cavities: structural and energetic consequences.

Marta Bueno1, Nunilo Cremades, José Luis Neira

  • 1Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Ciencias, Universidad de Zaragoza, 50009 Zaragoza, Spain.

Journal of Molecular Biology
|March 28, 2006
PubMed
Summary

Filling small cavities in proteins with larger residues can unexpectedly destabilize them. While larger cavities showed modest stabilization, smaller ones led to local unfolding, suggesting limited benefits for protein stability.

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Area of Science:

  • Protein engineering
  • Biophysics
  • Structural biology

Background:

  • Proteins often contain small internal cavities.
  • Replacing cavity-lining residues with larger ones is a strategy to potentially increase protein stability.
  • Hydrophobic core mutations that shorten protein structures typically decrease stability.

Purpose of the Study:

  • To investigate the impact of filling small cavities on protein structure and stability.
  • To determine if filling cavities in apoflavodoxin enhances protein stability.
  • To compare the effects of filling cavities of different sizes.

Main Methods:

  • Site-directed mutagenesis to fill cavities in apoflavodoxin.
  • Nuclear Magnetic Resonance (NMR) spectroscopy to assess protein structure.

Related Experiment Videos

  • Equilibrium unfolding analysis (urea and thermal denaturation) to measure protein stability.

    • Main Results:

    • Filling a small cavity (14 ų) resulted in local unfolding of mutant proteins.
    • Filling slightly larger cavities (20-21 ų) with Val to Ile/Leu mutations preserved the native fold.
    • Observed stabilizations (0.0–0.6 kcal mol⁻¹) were much smaller than theoretically predicted (approx. 1.5 kcal mol⁻¹).

    Conclusions:

    • Filling small cavities in proteins may not significantly increase stability due to necessary rearrangements.
    • The accommodation of additional volume in small cavities can introduce destabilizing effects.
    • Strategies to enhance protein stability by filling small, typical cavities are unlikely to yield large gains.