Conformational transition of Ab 42 inhibited by a mimetic peptide. A molecular modeling study using QM/MM calculations and QTAIM analysis

BARRERA EXEQUIEL; GUTIERREZ LUCAS JOEL; SALCEDO, RODRIGO; GARIBOTO FRANCISCO; ANDUJAR SEBASTIAN; ENRIZ, RICARDO D.; RODRIGUES, ANA MARÍA

Computational and Theoretical Chemistry

Elsevier

Año: 2016 vol. 1080 p. 56 - 65

2210-271X

The main pathogenic event in Alzheimer?s disease is believed to be the aggregation of the amyloidb-peptides into toxic aggregates. In a previous work we designed a mimetic peptide possessing asignificant aggregation modulating effect by means of a molecular modeling study, using a pentamericmodel as a molecular target. Considerable experimental evidence indicates that oligomers as small asdimers have been involved in this disease. Therefore, an alternative therapeutic strategy might be toblock the oligomerization at a monomeric level. To this end, using an Ab42monomeric model, weexplored the capacity and mechanism of our mimetic peptides to stabilize thea-helical conformationwhile preventing the formation ofb-sheet structures. Long time molecular dynamics simulations andMM?GBSA analysis were coupled to investigate this issue. In addition, a combined ONIOM?QTAIManalysis was used to identify at a quantum level the most relevant interactions between Ab42and thisinhibitor. The computational analysis presented here pointed out six important residues of Ab42(Lys16, Val36, Gly37, Gly38, Val39 and Val40) that strongly interact with our mimetic peptide, providingclues about the functional groups that might be modified in order to obtain more potent inhibitors