Impact of K16A and K28A mutation on the structure and dynamics of amyloid-β 42 peptide in Alzheimer's disease: Key insights from molecular dynamics simulations † .

The aggregation of amyloid-β42 (Aβ42 ) peptide into toxic oligomers and fibrils is a key step in the Alzheimer disease pathogenesis. The recent studies highlighted that lysine residues (K16 and K28) play a critical role in the Aβ42 self-assembly and are the target of entities like molecular tweezer, CLR01. The studies reveal that lysine to alanine mutation significantly affect Aβ oligomerization, toxicity and aggregation process. However, the molecular mechanism behind reduced Aβ toxicity on K16A and K28A mutation remain elusive. In this regard, molecular dynamics simulations were performed in the present study to get insights into the effect of K16A and K28A mutation in Aβ42 self-assembly. The molecular dynamics simulations highlighted that K16A and K28A mutation in the aggregation-prone region, i.e., central hydrophobic core (KLVFF, 16-20) and bend region (D23-K28), cause major structural changes in the Aβ42 monomer. The secondary structure analysis highlight that modulation of aggregation in K16A and K28A is linked to the increase in the overall helix content and a concomitant decrease in the β-sheet content of Aβ42 monomer. The short-range tertiary contacts between central hydrophobic core and C-terminal region were relatively reduced in K16A and K28A as compare to wild type (wt) Aβ42 . The mechanistic insights from the study will be beneficial for the design and development of novel inhibitors that will bind and block the interactions, mediated by lysine residues specifically, critical for the Aβ42 self-assembly in Alzheimer disease.