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

RODRIGO SALCEDO; EXEQUIEL E. BARRERA GUISASOLA; SEBASTIÁN A. ANDUJAR; LUCAS J. GUTIERREZ; ANA M. RODRÍGUEZ; RICARDO D. ENRIZ

Sierra de la Ventana

Congreso; XLIII Reunión anual de la Sociedad Argentina de Biofísica; 2014

We recently reported a new series of peptidomimeticcompounds with amyloid beta (A antiaggregant activity.These compounds were designed based on a molecularmodeling study using a pentameric A model as moleculartarget.Nα,Nε-Di-Z-L-lysinehydroxysuccinimideester(compound 7) was one of the compounds that showed the bestantiaggregant properties in the series. One question which ariseis: how this compound could affect the A monomer?. Toanswer this question we performed molecular dynamics (MD)simulations in both the monomer alone and the monomercomplexed with compound 7. Simulations were carried out inthree steps: 1) Compound 7 was docked into the monomerusing the program Autodock Vina (blind docking strategy). 2)We performed short MD simulations (10 ns each) to calculatethe relative binding energy of each complex using MolecularMechanics/Generalized Born Surface Area (MM/GBSA)method and 3) To explore the dynamic behaviour of thepreferred complex, more extensive MD simulations werecarried out in explicit water (300 ns sampling time).Simulations were compared with those obtained for themonomer alone.