INVESTIGADORES
ANDUJAR Sebastian Antonio
artículos
Título:
Amyloid-b fibril disruption by C60?molecular guidance for rational drug design
Autor/es:
SEBASTIAN A. ANDUJAR; FRANCESCA LUGLI; SIEGFRIED HOFINGER; FRANCESCO ZERBETTO; RICARDO D. ENRIZ
Revista:
PHYSICAL CHEMISTRY CHEMICAL PHYSICS
Editorial:
ROYAL SOC CHEMISTRY
Referencias:
Lugar: CAMBRIDGE; Año: 2012 vol. 14 p. 8599 - 8607
ISSN:
1463-9076
Resumen:
The WHO has listed Alzheimer?s disease among the major neurological disorders with an
estimated 35 million people affected worldwide. Amyloid-b is mostly believed to be the causative
factor in Alzheimer?s disease and the severity of the disease correlates with the tendency of
amyloid-b to form aggregation patterns?plaques. Lacking effective medication, the identification
of any underlying mechanistic principles regarding plaque formation appears to be crucial. Here
we carry out computer simulations to study the effect of C60 on structure and stability of an
idealised pentameric construct of amyloid-b units (a model fibril). A binding site on top of the
structurally ordered stack of b-sheets is identified that triggers structural alterations at the turn
region of the hook-like b-sheet assembly. Significant structural alterations are: (i) the destruction
of regular helical twist, (ii) the loss of a stabilizing salt bridge and (iii) the loss of a stabilizing
hydrophobic interaction close to the turn. Consequently, the main effect of C60 is the induction of
sizable destabilization in native fibril structure. These structural insights may serve as a molecular
guide for further rational drug design of effective inhibitors targeting fibril formation in
Alzheimer?s disease.