Unraveling the structural dynamics of Aβ42 monomer: insights from K16A and K16A + K28A mutations through molecular dynamics simulations.

Abstract

Alzheimer's disease is a degenerative disease of the central nervous system that pre-dominantly affects the elderly population. The main reason is that amyloid beta 42 has a strong tendency to aggregate, which easily induces the damage to the central nervous system. It was shown that residues 16 and 28 play a key role in the self-assembly process. Moreover, these studies have revealed that substituting alanine for these residues can weaken the toxicity of Aβ. While numerous studies,including molecular dynamics simulations, have emphasized the significance of K16 and K28 in Aβ aggregation and toxicity, the specific impact of their combined mutation(K16A + K28A) on the structural dynamics and toxicity of Aβ remain unclear. Therefore, in this paper, molecular dynamics simulations were used to investigate the structural changes and kinetic properties of Aβ42 protein by the two mutant systems. The results show that both mutant systems inhibit the high flexibility of wild-type Aβ protein during the simulation. By observing the changes in protein structure in different systems, it is found that the K16A system was able to maintain the natural helical conformation of Aβ42 and also inhibit the generation of β-sheet structures. However, for the K16A + K28A system, it not only destroys the helical structure, but also produces more β-sheet structures. The analysis of residue contacts revealed that this phenomenon. The K16A system was able to decrease the interaction between the hp1fragment and the C-terminus in the Aβ42 monomer, whereas the two-point mutation increased this interaction.