Proline isomerization effects in the amyloidogenic protein β₂-microglobulin

Area of Science:

• Biochemistry
• Molecular Biology
• Biophysics

Background:

• Beta-2 microglobulin (β2-m) forms amyloid fibrils in patients on long-term hemodialysis.
• The molecular basis of β2-m amyloidogenesis remains incompletely understood.
• Proline 32 (Pro32) cis-trans isomerization is a proposed, though debated, trigger for β2-m aggregation.

Purpose of the Study:

• To investigate the cis-trans isomerization mechanism of Pro32 in native and mutant β2-m.
• To elucidate the role of protein interactions in stabilizing β2-m isomers.
• To provide molecular insights into β2-m amyloid formation relevant to dialysis-associated amyloidosis.

Main Methods:

• Molecular dynamics (MD) simulations.
• Metadynamics enhanced sampling method.
• Free energy calculations for cis and trans isomers.

Main Results:

• Simulations accurately reproduced experimental findings.
• Identified key hydrogen bond and hydrophobic interactions around Pro32.
• These interactions stabilize or destabilize the cis and trans isomers of β2-m.

Conclusions:

• The study provides a detailed molecular mechanism for Pro32 isomerization in β2-m.
• Highlights the critical role of specific interactions in protein conformational changes.
• Offers insights into the early events of β2-m amyloidogenesis in dialysis patients.