Conformational transition of Aβ42 inhibited by a mimetic peptide. A molecular modeling study using QM/MM calculations and QTAIM analysis

The main pathogenic event in Alzheimer's disease is believed to be the aggregation of the amyloid beta-peptides into toxic aggregates. In a previous work we designed a mimetic peptide possessing a significant aggregation modulating effect by means of a molecular modeling study, using a pentameric model as a molecular target. Considerable experimental evidence indicates that oligomers as small as dimers have been involved in this disease. Therefore, an alternative therapeutic strategy might be to block the oligomerization at a monomeric level. To this end, using an AN, monomeric model, we explored the capacity and mechanism of our mimetic peptides to stabilize the alpha-helical conformation while preventing the formation of beta-sheet structures. Long time molecular dynamics simulations and MM-GBSA analysis were coupled to investigate this issue. In addition, a combined ONIOM-QTAIM analysis was used to identify at a quantum level the most relevant interactions between A beta(42) and this inhibitor. The computational analysis presented here pointed out six important residues of A beta(42) (Lys16, Val36, Gly37, Gly38, Val39 and Va140) that strongly interact with our mimetic peptide, providing clues about the functional groups that might be modified in order to obtain more potent inhibitors. (C) 2016 Elsevier B.V. All rights reserved.