Electrostatics-Induced Nucleated Conformational Transition of Protein Aggregation

Area of Science:

• Biophysics
• Chemical Physics
• Molecular Biology

Background:

• Protein aggregation is prevalent in nature and implicated in numerous human diseases.
• The precise molecular mechanisms driving protein aggregation remain incompletely understood.

Purpose of the Study:

• To develop a molecular theory elucidating the mechanism of protein aggregation.
• To investigate the role of electrostatic interactions and salt concentration on aggregation pathways and aggregate morphology.

Main Methods:

• Incorporation of self-consistent field theory for charged macromolecules into dilute solution thermodynamics.
• Tracking the kinetic pathway of aggregation without morphological restrictions.
• Utilizing scaling analysis to understand electrostatic contributions.

Main Results:

• At low salt concentrations, protein aggregation proceeds via a two-step nucleation mechanism.
• A conformational transition from metastable spherical oligomers to elongated fibrils is observed, driven by electrostatic interactions.
• Increased salt concentration leads to a recovery of the classical one-step nucleation pathway, resembling liquid-liquid phase separation.

Conclusions:

• Screened electrostatic interactions are crucial for the formation of metastable oligomers and their subsequent transition to fibrils.
• The developed molecular theory accurately predicts the kinetic pathways and aggregate morphologies observed in experimental studies of real proteins.