Interfacial Dynamics and Growth Modes of β₂-Microglobulin Dimers

Area of Science:

• Biophysics
• Computational Biology
• Protein Science

Background:

• Protein aggregation is a complex, environmentally sensitive process.
• Dimer formation is the initial step in protein self-association.
• Understanding dimer properties is crucial for predicting aggregation.

Purpose of the Study:

• To develop a simple model and computational method to investigate how dimer interfacial properties influence protein growth modes.
• To analyze the impact of dimer interface modulations on aggregation pathways.
• To identify factors governing limited versus unlimited protein growth.

Main Methods:

• A computational model representing dimer interfaces using two angles.
• Analysis of 15 dimer configurations of β2m D76N mutant protein using Molecular Dynamics simulations.
• Investigation of ns-μs time scale modulations on dimer growth modes.

Main Results:

• Most polymeric growth modes are conserved over the studied time scale, despite dynamic dimer configurations.
• The model successfully accounts for the nonspherical morphology and weak binding affinities of β2m dimers.
• Specific dimer interfaces were identified that lead to limited and unlimited growth modes.

Conclusions:

• The proposed methodology effectively predicts protein aggregation profiles based on dimer interface characteristics.
• The approach is general and applicable to various proteins with known or predicted dimer structures.
• Dimer interfacial geometry and stability are key determinants of protein aggregation pathways.