Molecular insight into conformational transition of amyloid β-peptide 42 inhibited by Nα,Nε-Di-Z-L-lysine hydroxysuccinimide ester probed by molecular simulations

SALCEDO, RODRIGO; BARRERA, EXEQUIEL; ANDUJAR SEBASTIAN; GUTIÉRREZ LUCAS J.; RODRIGUES, ANA MARÍA; ENRIZ, RICARDO D.

Congreso; XLIII Reunión Anual SAB 2014; 2014

Molecular insight into conformational transition of amyloid β-peptide 42 inhibited by Nα,Nε-Di-Z-L-lysine hydroxysuccinimide ester probed by molecular simulations Salcedo, R.ab; Barrera, E.ab ; Andujar, S.ab ; Gutierrez, L.ab ; Rodríguez, A.M.ab ; Enriz, D. ab aFacultad de Quíica Bioquímica y Farmacia, Universidad Nacional de San Luis, Chacabuco 915, 5700 San Luis, Argentina. bIMIBIO-SL (CONICET), Chacabuco 915, 5700 San Luis, Argentina c Facultad de Ciencias Exactas y Naturales y Agrimensura, Universidad Nacional del Nordeste We recently reported a new series of peptidomimetic compounds with amyloid beta (Ab) antiaggregant activity. These compounds were designed based on a molecular modeling study using a pentameric Ab model as molecular target. Nα,Nε-Di-Z-L-lysine hydroxysuccinimide ester (compoud 7) was one of the compounds that showed the best antiaggregant properties in the series. One question which arise is: what effect would this compound in the Ab monomer?. To answer this question we performed molecular dynamic (MD) simulations in both the monomer alone and the monomer complexed with compound 7. Simulations were carried out in three steps: 1) Compound 7 was docked into the monomer using the program Autodock Vina (blind docking strategy). 2) We performed short MD simulations (10 ns each) to calculate the relative binding energy of each complex using Molecular Mechanics/Poisson Boltzman Surface Area (MM/PBSA) method and 3) To explore the dynamic behaviour of the preferred complexes, more extensive MD simulations were carried out in explicit water (300 ns sampling time). Simulations were compared with those obtained for the monomer alone. Three distinct binding sites were identified for compound 7 at the monomer, being the zone located between residues Gln15 and Asp23 the preferred site for binding. From our simulations it is possible to observe that compound 7 substantially maintained the helix forms preventing the conformational transition of the Ab monomer necessary for its oligomerization.