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Updated: Aug 4, 2026

Analysis of β-Amyloid-induced Abnormalities on Fibrin Clot Structure by Spectroscopy and Scanning Electron Microscopy
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Analysis of β-Amyloid-induced Abnormalities on Fibrin Clot Structure by Spectroscopy and Scanning Electron Microscopy

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Characterization of two distinct beta2-microglobulin unfolding intermediates that may lead to amyloid fibrils of

Roger S Armen1, Valerie Daggett

  • 1Biomolecular Structure and Design Program, University of Washington, Seattle, Washington 98195-7610, USA.

Biochemistry
|December 8, 2005
PubMed

Insights

Beta(2)-microglobulin self-assembly into amyloid fibrils causes dialysis-related amyloidosis. Molecular dynamics simulations reveal two distinct partially unfolded intermediates, potentially explaining different fibril structures.

Area of Science:

  • Biochemistry
  • Structural Biology
  • Computational Biophysics

Background:

  • Dialysis-related amyloidosis is caused by beta(2)-microglobulin fibril formation.
  • Partial unfolding of beta(2)-microglobulin at specific pH is crucial for amyloidogenic intermediate formation.
  • Experimental characterization of these partially unfolded states is challenging.

Purpose of the Study:

  • To determine the high-resolution structures of partially unfolded amyloidogenic intermediates of beta(2)-microglobulin.
  • To elucidate the role of pH in the conformational changes leading to fibril formation.
  • To identify distinct intermediate states and their potential link to fibril morphology.

Main Methods:

  • Molecular dynamics simulations were conducted at neutral and low pH.
  • Multiple simulations were performed to ensure robust identification of conformational ensembles.
  • Analysis focused on structural features, including secondary structure formation and hydrophobic interactions.

Main Results:

  • Two distinct intermediate state ensembles were identified at low pH.
  • The predominant early intermediate resembled native beta(2)-microglobulin.
  • A late unfolding intermediate was disordered yet elongated, with hydrophobic clusters and residual alpha-sheet structures.
  • Formation of alpha-sheet structure was observed, consistent with Pauling and Corey's proposals.

Conclusions:

  • The identified intermediate states may explain the formation of fibrils with distinct morphologies.
  • The proposed alpha-sheet structure facilitates self-assembly into prefibrillar amyloidogenic intermediates.
  • These findings provide structural insights into the mechanism of dialysis-related amyloidosis.

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