Carbon Nanotube Inhibits the Formation of β-Sheet-Rich Oligomers of the Alzheimer's Amyloid-β(16-22) Peptide

Abstract

Alzheimer's disease is associated with the abnormal self-assembly of the amyloid-β (Aβ) peptide into toxic β-rich aggregates. Experimental studies have shown that hydrophobic nanoparticles retard Aβ fibrillation by slowing down the nucleation process; however, the effects of nanoparticles on Aβ oligomeric structures remain elusive. In this study, we investigate the conformations of Aβ(16-22) octamers in the absence and presence of a single-walled carbon nanotube (SWCNT) by performing extensive all-atom replica exchange molecular-dynamics simulations in explicit solvent. Our simulations starting from eight random chains demonstrate that the addition of SWCNT into Aβ(16-22) solution prevents β-sheet formation. Simulation starting from a prefibrillar β-sheet octamer shows that SWCNT destabilizes the β-sheet structure. A detailed analysis of the Aβ(16-22)/SWCNT/water interactions reveals that both the inhibition of β-sheet formation and the destabilization of prefibrillar β-sheets by SWCNT result from the same physical forces: hydrophobic and π-stacking interactions (with the latter playing a more important role). By analyzing the stacking patterns between the Phe aromatic rings and the SWCNT carbon rings, we find that short ring-centroid distances mostly favor parallel orientation, whereas large distances allow all other orientations to be populated. Overall, our computational study provides evidence that SWCNT is likely to inhibit Aβ(16-22) and full-length Aβ fibrillation.

Modeling and simulation of protein–surface interactions: achievements and challenges

“…REMD methods are useful to sample a large set of configurations in different potential wells separated by high energy barriers, which otherwise is not possible in a classical MD simulation. Indeed, temperature-based REMD (T-REMD) simulations were used in several studies to accelerate the sampling of peptide-surface interactions Li et al 2011;Oren et al 2010) and of interactions of basic fibroblast growth factor (bFGF), a small protein, with a hydroxyapatite (001) surface (Liao & Zhou, 2014). Liao and Zhou observed that while the protein displaces the surface hydration shell and binds tightly to the surface in the T-REMD simulations (five replicas in the range from 310 K to 2500 K), bFGF did not contact the surface directly in classical MD simulations at 310 K (Liao & Zhou, 2014).…”

Specific Binding of Alzheimer's Aβ Peptide Fibrils to Single-Walled Carbon Nanotubes

“…Fullerenes were shown to inhibit fibril formation by binding to the hydrophobic KLVFF sequence [21], while multiwalled carbon nanotubes and graphite were shown to promote their formation [19,64]. However, computer simulations have suggested that SWCNTs can inhibit the formation of amyloid from Aβ peptide fragments 16-22 and 25-35 [65,66], demonstrating that further studies are required to address this issue.…”

Environmental impact of multi-wall carbon nanotubes in a novel model of exposure: systemic distribution, macrophage accumulation, and amyloid deposition

“…48,49 This primitive defense mechanism employed by cells to aggregate melanin, [37][38][39][40][48][49][50] a strategy employed to build a scaffold for melanin assembly, forming at least a barrier against pathogens or foreign bodies, 48,49 has been recently associated with oxidative damage and inflammation in several different types of cells. 49 We demonstrate the presence of amyloid in lung, liver, and brain of MWCNT-exposed mice.…”

“…36 In this context, data concerning the ability of CNTs to induce protein aggregation and amyloid fiber formation are controversial. [37][38][39][40] The NLRP3 inflammasome, associated with immune responses to CNTs, [27][28][29][30]41 activates release of IL-18, 42 a cytokine associated with amyloid plaque formation in Alzheimer's disease, [43][44][45][46] a neurodegenerative disorder characterized by amyloid accumulation. For these reasons, we investigated the ability of CNTs to induce amyloid production and deposition in vivo, an innate defense mechanism present in most eukaryotic phyla ranging from fungi and invertebrates [47][48][49] to humans.…”