Journal of Molecular Graphics and Modelling ( IF 2.9 ) Pub Date : 2021-03-09 , DOI: 10.1016/j.jmgm.2021.107889 Pavan Krishna Kanchi 1 , Ashok Kumar Dasmahapatra 2
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.
中文翻译:
THC破坏阿尔茨海默氏症淀粉样β原纤维的分子动力学模拟研究
阿尔茨海默氏病是目前尚无治愈方法的老年人口痴呆症的主要原因。在患者的大脑中发现了神经毒性斑块的沉积物,这些斑块由淀粉样β肽的原纤维组成。可以破坏这些原纤维的分子作为潜在的治疗剂已受到关注。Δ-四氢大麻二酚(THC)是一种大麻素,可以与大脑中的受体结合,并且在许多实验研究中都显示出减少原纤维含量的希望。在我们目前的研究中,通过采用所有原子分子动力学模拟,我们研究了THC分子与β-淀粉样原纤维相互作用的机理。我们的结果表明,THC分子通过与原纤维牢固结合而破坏了原纤维的结构。结合的驱动力是与原纤维中的疏水残基的疏水相互作用。这些相互作用的结果是,原纤维疏水核的紧密堆积被松散了,并且破坏了对稳定性至关重要的盐桥。对于稳定性而言重要的原纤维链之间的氢键被破坏,其结果是减少了β-折叠的含量。THC分子对原纤维的去稳定作用得出结论,认为THC分子可考虑用于治疗阿尔茨海默氏病。对于稳定性而言重要的原纤维链之间的氢键被破坏,其结果是减少了β-折叠的含量。THC分子对原纤维的去稳定作用得出结论,认为THC分子可考虑用于治疗阿尔茨海默氏病。对于稳定性而言重要的原纤维链之间的氢键被破坏,其结果是减少了β-折叠的含量。THC分子对原纤维的去稳定作用得出结论,认为THC分子可考虑用于治疗阿尔茨海默氏病。