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How internal cavities destabilize a protein.

Mengjun Xue1,2, Takuro Wakamoto3, Camilla Kejlberg1,2

  • 1Interdisciplinary Nanoscience Center, University of Aarhus, 8000 Aarhus C, Denmark.

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|October 2, 2019
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Summary
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Pressure perturbation NMR reveals hidden protein excited states. This method quantifies the energetic cost of internal cavities within proteins, crucial for understanding protein folding and function.

Keywords:
high-pressure NMRprotein folding and cooperativityprotein stabilityunfolded state

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Area of Science:

  • Biophysics
  • Structural Biology
  • Protein Dynamics

Background:

  • Proteins exist in a dynamic equilibrium, accessing low-lying excited states beyond their stable folded structure.
  • These excited states are vital for biological function but remain structurally uncharacterized due to their low populations.
  • Protein misfolding and aggregation are linked to transitions into these excited states.

Purpose of the Study:

  • To characterize the structure and energetics of elusive protein excited states.
  • To investigate the role of internal cavities in protein stability and dynamics.
  • To develop and apply pressure perturbation NMR techniques for studying excited states.

Main Methods:

  • Nuclear Magnetic Resonance (NMR) spectroscopy combined with pressure perturbation.
  • Relaxation dispersion NMR to monitor pressure-induced population changes in specific folded states.
  • Pressure-dependent Hydrogen/Deuterium (H/D) exchange NMR to detect partly disordered excited states.

Main Results:

  • Pressure increases the population of a previously 'invisible' folded excited state in T4 lysozyme L99A by reducing internal cavity volume.
  • Multiple partly disordered excited states were identified at equilibrium via pressure-dependent H/D exchange NMR.
  • A direct correlation was observed between the pressure sensitivity of protein regions and the loss of internal cavity volume during unfolding.
  • The energetic penalty of empty internal protein cavities was quantified at 36 cal⋅Å-3.

Conclusions:

  • Pressure perturbation NMR is a powerful tool for characterizing transient and low-population protein excited states.
  • Internal cavities significantly contribute to protein energetics, with a quantifiable penalty for their existence.
  • Understanding excited states and internal cavity energetics is key to elucidating protein folding, function, and disease-related aggregation.