Destabilization of the Alzheimer's amyloid-β protofibrils by THC: A molecular dynamics simulation study

J Mol Graph Model. 2021 Jun:105:107889. doi: 10.1016/j.jmgm.2021.107889. Epub 2021 Mar 9.


Alzheimer's disease is a leading cause of dementia in the elderly population for which there is no cure at present. Deposits of neurotoxic plaques are found in the brains of patients which are composed of fibrils of the amyloid-β peptide. Molecules which can disrupt these fibrils have gained attention as potential therapeutic agents. Δ-tetrahydrocannabidiol (THC) is a cannabinoid, which can bind to the receptors in the brain, and has shown promise in reducing the fibril content in many experimental studies. In our present study, by employing all atom molecular dynamics simulations, we have investigated the mechanism of the interaction of the THC molecules with the amyloid-β protofibrils. Our results show that the THC molecules disrupt the protofibril structure by binding strongly to them. The driving force for the binding was the hydrophobic interactions with the hydrophobic residues in the fibrils. As a result of these interactions, the tight packing of the hydrophobic core of the protofibrils was made loose, and salt bridges, which were important for stability were disrupted. Hydrogen bonds between the chains of the protofibrils which are important for stability were disrupted, as a result of which the β-sheet content was reduced. The destabilization of the protofibrils by the THC molecules leads to the conclusion that THC molecules may be considered for the therapy in treating Alzheimer's disease.

Keywords: Alzheimer’s disease; Amyloid-β fibril; Molecular dynamics simulations; Δ-tetrahydrocannabidiol (THC).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Alzheimer Disease* / drug therapy
  • Amyloid beta-Peptides
  • Humans
  • Hydrogen Bonding
  • Molecular Dynamics Simulation*
  • Peptide Fragments
  • Protein Conformation, beta-Strand


  • Amyloid beta-Peptides
  • Peptide Fragments