The Inhibitory Effect of Hydroxylated Carbon Nanotubes on the Aggregation of Human Islet Amyloid Polypeptide Revealed by a Combined Computational and Experimental Study

ACS Chem Neurosci. 2018 Nov 21;9(11):2741-2752. doi: 10.1021/acschemneuro.8b00166. Epub 2018 Jul 23.

Abstract

Fibrillar deposits formed by the aggregation of the human islet amyloid polypeptide (hIAPP) are the major pathological hallmark of type 2 diabetes mellitus (T2DM). Inhibiting the aggregation of hIAPP is considered the primary therapeutic strategy for the treatment of T2DM. Hydroxylated carbon nanoparticles have received great attention in impeding amyloid protein fibrillation owing to their reduced cytotoxicity compared to the pristine ones. In this study, we investigated the influence of hydroxylated single-walled carbon nanotubes (SWCNT-OHs) on the first step of hIAPP aggregation: dimerization by performing explicit solvent replica exchange molecular dynamics (REMD) simulations. Extensive REMD simulations demonstrate that SWCNT-OHs can dramatically inhibit interpeptide β-sheet formation and completely suppress the previously reported β-hairpin amyloidogenic precursor of hIAPP. On the basis of our simulation results, we proposed that SWCNT-OH can hinder hIAPP fibrillation. This was further confirmed by our systematic turbidity measurements, thioflavin T fluorescence, circular dichroism (CD), transmission electron microscope (TEM), and atomic force microscopy (AFM) experiments. Detailed analyses of hIAPP-SWCNT-OH interactions reveal that hydrogen bonding, van der Waals, and π-stacking interactions between hIAPP and SWCNT-OH significantly weaken the inter- and intrapeptide interactions that are crucial for β-sheet formation. Our collective computational and experimental data reveal not only the inhibitory effect but also the inhibitory mechanism of SWCNT-OH against hIAPP aggregation, thus providing new clues for the development of future drug candidates against T2DM.

Keywords: TEM experiment; human islet amyloid polypeptide; hydroxylated carbon nanotubes; inhibitory mechanism; protein aggregation; replica exchange molecular dynamics simulations.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid / metabolism*
  • Amyloid / ultrastructure
  • Circular Dichroism
  • Computer Simulation
  • Diabetes Mellitus, Type 2 / metabolism*
  • Diabetes Mellitus, Type 2 / pathology
  • Humans
  • Hydroxylation
  • In Vitro Techniques
  • Inverted Repeat Sequences
  • Islet Amyloid Polypeptide / metabolism*
  • Islet Amyloid Polypeptide / ultrastructure
  • Microscopy, Atomic Force
  • Microscopy, Electron, Transmission
  • Molecular Dynamics Simulation
  • Nanotubes, Carbon*
  • Protein Aggregation, Pathological / metabolism*
  • Protein Aggregation, Pathological / pathology
  • Protein Conformation, beta-Strand

Substances

  • Amyloid
  • Islet Amyloid Polypeptide
  • Nanotubes, Carbon