Conformational Fluctuations in β2-Microglubulin Using Markov State Modeling and Molecular Dynamics

Area of Science:

• Biochemistry
• Protein Dynamics
• Molecular Biology

Background:

• Protein misfolding and aggregation are implicated in various diseases.
• Beta2-microglobulin (β2m) is known to aggregate, contributing to amyloidosis.

Purpose of the Study:

• To investigate the intermediate and near-folded states of β2m.
• To elucidate the physico-chemical properties driving β2m aggregation.

Main Methods:

• Molecular dynamics simulations.
• Markov state modeling.
• Analysis of hundreds of microseconds of simulation data.

Main Results:

• Identified critical role of edge strands in misfolded β2m states.
• Observed high exposure of hydrophobic residues in the protein core.
• These exposed residues initiate oligomerization and aggregate formation.

Conclusions:

• The study illuminates the initial steps of β2m monomer aggregation.
• Provides a clearer understanding of the protein misfolding and aggregation landscape.