Predicting stable binding modes from simulated dimers of the D76N mutant of 2-microglobulin

Area of Science:

• Biochemistry
• Molecular Biology
• Computational Biology

Background:

• The D76N mutant of the protein serves as a model for studying protein aggregation.
• Experimental and simulation data indicate D76N populates a dynamic conformation exposing aggregation-prone regions due to terminal region detachment.

Purpose of the Study:

• Investigate the stability of protein dimers formed by the D76N mutant.
• Analyze the structural basis of dimer interface stabilization.
• Determine the oligomerization potential of stable D76N dimer interfaces.

Main Methods:

• Molecular Dynamics (MD) simulations to study dimer stability.
• Protein-protein docking to generate dimer ensembles.
• Molecular Mechanics with the Poisson-Boltzmann and Solvent Accessible Surface Area (MM-PBSA) calculations for binding energy assessment.
• Geometric rule-based propagation of dimer interfaces.

Main Results:

• Hydrophobic interactions are the primary drivers of dimer interface stabilization at physiological pH.
• The most stable dimer interfaces involve N- and C-termini, and BC/DE-loops.
• Less stable interfaces are stabilized by CD/EF-loop interactions.
• Propagation of the most stable interfaces suggests a self-limited growth process, not indefinite polymerization.

Conclusions:

• D76N dimer stability is governed by specific residue interactions, particularly hydrophobic forces.
• The structural characteristics of the most stable D76N dimer interfaces inherently limit further polymerization.
• This finding has implications for understanding and potentially controlling protein aggregation pathways.