Mathematical Modeling of Aβ-42 Dimerization Dynamics: Integrating Physics-Based Simulations, Graph-Based Variational...

Area of Science:

• Computational biophysics
• Neurodegenerative disease research
• Pharmacological modeling

Background:

• Alzheimer's disease (AD) is linked to amyloid-beta (Aβ) peptide aggregation, especially Aβ-42.
• Soluble Aβ dimers are considered key neurotoxic species causing synaptic dysfunction and cognitive decline.

Purpose of the Study:

• To investigate the molecular mechanisms of Aβ-42 dimerization.
• To evaluate apigenin and caffeine as potential inhibitors of Aβ-42 aggregation.

Main Methods:

• Molecular dynamics (MD) simulations to observe Aβ-42 interactions.
• Neural relational inference (NRI) modeling to analyze residue interactions.
• Largest Lyapunov exponent (LLE) analysis to assess dynamic stability.

Main Results:

• Apigenin demonstrated superior inhibition of Aβ-42 aggregation compared to caffeine.
• MD simulations and MM/GBSA calculations showed apigenin destabilizes key aggregation-prone residues (29-30).
• NRI confirmed apigenin reduces inter-residue interactions, preventing β-sheet formation; LLE analysis showed stabilization of monomeric Aβ-42.

Conclusions:

• Apigenin effectively inhibits Aβ-42 dimerization by disrupting critical interactions and stabilizing monomeric forms.
• This study provides mechanistic insights into Aβ-42 aggregation inhibition.
• Apigenin emerges as a promising therapeutic candidate for Alzheimer's disease targeting early aggregation stages.