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.