Unraveling the structural dynamics of A <i>β</i> 42 monomer: insights from K16A and K16A + K28A mutations through molecular dynamics simulations

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 A<i>β</i>. While numerous studies,including molecular dynamics simulations, have emphasized the significance of K16 and K28 in A<i>β</i> aggregation and toxicity, the specific impact of their combined mutation(K16A + K28A) on the structural dynamics and toxicity of A<i>β</i> remain unclear. Therefore, in this paper, molecular dynamics simulations were used to investigate the structural changes and kinetic properties of A<i>β</i>42 protein by the two mutant systems. The results show that both mutant systems inhibit the high flexibility of wild-type A<i>β</i> 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 A<i>β</i>42 and also inhibit the generation of <i>β</i>-sheet structures. However, for the K16A + K28A system, it not only destroys the helical structure, but also produces more <i>β</i>-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 A<i>β</i>42 monomer, whereas the two-point mutation increased this interaction.