Concentration Effect, Structural Properties, and Driving Force on Aβ₂₈ Dimerization with and without Zn²⁺...

Area of Science:

• Biochemistry and Molecular Biology
• Neuroscience
• Computational Chemistry

Background:

• Zinc ions (Zn²⁺) are implicated in the formation of amyloid beta (Aβ) aggregates and plaques, crucial in neurodegenerative diseases.
• Zn²⁺-bound Aβ species tend to form amorphous or low molecular-weight oligomers.
• Understanding the initial dimerization steps in Aβ nucleation, particularly with and without Zn²⁺, is vital for elucidating Zn²⁺-induced nucleation mechanisms.

Purpose of the Study:

• To investigate the structural properties, concentration effects, and driving forces of Aβ₂₈ dimerization with and without Zn²⁺.
• To elucidate the role of Zn²⁺ in the early stages of Aβ nucleation.
• To identify specific residues and molecular interactions involved in Zn²⁺-mediated Aβ₂₈ dimerization.

Main Methods:

• Employed 14 independent replica exchange molecular dynamics simulations.
• Simulated Aβ₂₈ dimerization in three systems: Aβ₂₈-Aβ₂₈, Aβ₂₈-zAβ₂₈, and zAβ₂₈-zAβ₂₈.
• Analyzed aggregation propensity, binding properties, and specific residue interactions (H13, H14).

Main Results:

• Aggregation propensity was higher in Aβ₂₈-Aβ₂₈ and Aβ₂₈-zAβ₂₈ systems compared to zAβ₂₈-zAβ₂₈.
• The binding affinity was strongest for Aβ₂₈-Aβ₂₈ (-61.5 kcal/mol), followed by zAβ₂₈-zAβ₂₈ (-26.6 kcal/mol) and Aβ₂₈-zAβ₂₈ (-7.24 kcal/mol).
• Histidine residues H13 and H14, specifically the orientation of the imidazole ring's N atom, play critical roles, with distinct driving forces identified for each system.

Conclusions:

• The study provides insights into the interaction of Aβ₂₈ dimers with Zn²⁺ at the molecular level.
• Zn²⁺ binding significantly alters the dimerization process and binding strength of Aβ₂₈.
• Findings contribute to a deeper understanding of Zn²⁺-induced nucleation mechanisms in amyloid formation.