Characterizing the structural behavior of selected Aβ-42 monomers with different solubilities

Area of Science:

• Biochemistry
• Molecular Biology
• Computational Chemistry

Background:

• Amyloid beta-42 (Aβ-42) peptide aggregation is central to Alzheimer's disease pathogenesis.
• Understanding monomer conformational dynamics is crucial for identifying early-stage oligomerization triggers.

Purpose of the Study:

• To investigate the structural features of wild-type Aβ-42 and its mutants that influence oligomerization.
• To identify specific structural determinants promoting or inhibiting early Aβ-42 oligomerization.

Main Methods:

• All-atom replica exchange molecular dynamics simulations in explicit solvent.
• Analysis of peptide flexibility, preferential structures, and rigidity using computational markers.

Main Results:

• Wild-type Aβ-42 and mutants display distinct conformational preferences and rigidity.
• A mutant peptide, experimentally found to remain monomeric, exhibits enhanced N-terminal structural rigidity.
• N-terminal structural stabilization correlates with reduced Aβ oligomerization and toxicity.

Conclusions:

• The N-terminal region of Aβ-42 plays a significant role in modulating its oligomerization propensity.
• Specific point mutations can induce pronounced structural changes affecting Aβ aggregation.
• Findings provide insights into Aβ-42 structural dynamics and potential therapeutic targets for Alzheimer's disease.