Amyloid-β fibril disruption by C60—molecular guidance for rational drug design

Abstract

The WHO has listed Alzheimer's disease among the major neurological disorders with an estimated 35 million people affected worldwide. Amyloid-β is mostly believed to be the causative factor in Alzheimer's disease and the severity of the disease correlates with the tendency of amyloid-β 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-β units (a model fibril). A binding site on top of the structurally ordered stack of β-sheets is identified that triggers structural alterations at the turn region of the hook-like β-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.

Dimensionality of Carbon Nanomaterials Determines the Binding and Dynamics of Amyloidogenic Peptides: Multiscale Theoretical Simulations

“…The results show that the presence of C60 inhibits the formation of the characteristic fibril favoring β-hairpin as well as the extended conformation suggesting that the interactions with the C60 may contribute to an increase in mobility (see Figure S1) and facilitate the formation of fibril incompetent conformations. Recent work by Andujar et al where they showed that C60 induced significant destabilization of the amyloid-β fibrils by disrupting the hydrophobic contacts and salt-bridges between the β-sheets [76] is in line with our work. This suggests that C60 can be used as a prototype for the design of potential fibril inhibitors.…”

Molecular insight into amyloid oligomer destabilizing mechanism of flavonoid derivative 2-(4′ benzyloxyphenyl)-3-hydroxy-chromen-4-one through docking and molecular dynamics simulations

“…Small natural molecules, vitamin analogues, drugs like naproxen, ibuprofen were studied against AD and for their inhibitory mechanism (Lemkul et al, 2010;Takeda et al, 2010;Choi et al, 2008;Andujar et al, 2012;Huy et al, 2013;Richard et al, 2013 ). However, the interaction of various destabilizing agents with amyloid oligomer and their mechanism is still largely unknown (Lemkul et al, 2010;Takeda et al, 2010).…”

Aβ self-association and adsorption on a hydrophobic nanosurface: competitive effects and the detection of small oligomers via electrical response

“…23,24 However, structural information on the monomeric and various self-assembled forms has been obtained via NMR methods. [35][36][37][38][39] Kim and Lee rst showed that 1,2-(dimethoxylmethano) fullerene specically binds to the KLVFF region of the Ab protein, thereby suppressing Ab aggregation. 7,18,[26][27][28][29][30] Non-covalent interactions arising from various nanomaterials could be harnessed for modulating the intrinsic selfassembly characteristics of Ab.…”