Concentration Effect, Structural Properties, and Driving Force on Aβ28 Dimerization with and without Zn2+ Cooperation: Learning from Replica Exchange Sampling

Abstract

Zn²⁺ is a very important factor in promoting the formation of amyloid beta (Aβ) aggregates and amyloid plaques. The Zn²⁺ -bound Aβ species generate amorphous or low molecular-weight oligomers. However, it is a lack of studies to approach the starting structural features (dimerization) in Aβ nucleation processes with and without Zn²⁺ , which is the key point in understanding Zn²⁺ -induced nucleation mechanisms. To better understand the effect of concentration, structural properties, and the driving force, 14 independent replica exchange molecular dynamics simulations were performed in Aβ₂₈ dimerization with and without Zn²⁺ (zAβ₂₈ ) cooperation. Our scanning results show that the aggregation propensity is easier in Aβ₂₈ -Aβ₂₈ and Aβ₂₈ -zAβ₂₈ systems than zAβ₂₈ -zAβ₂₈ system. In binding property, the Aβ₂₈ -Aβ₂₈ model (-61.5 kcal mol^-1 ) is stronger than zAβ₂₈ -zAβ₂₈ (-26.6 kcal mol^-1 ) and Aβ₂₈ -zAβ₂₈ (-7.24 kcal mol^-1 ) models. Further analysis confirmed that H13 and H14 residues play specific roles in the three systems. The key point is the orientation of N atom of the imidazole ring in histidine residues. Furthermore, we discovered different driving forces for each system. Our current study contributes to the understanding of how the Aβ₂₈ dimer interacts with Zn²⁺ , which could lead to new insights into Zn²⁺ -induced nucleation mechanisms.

Keywords: AD pathogenesis; aggregation mechanism; histidine behavior; metal ions effect; protein folding and misfolding.