Department of Chemistry, Faculty of Basic and Applied Sciences, Sri Guru Granth Sahib World University, Fatehgarh Sahib-140406, Punjab, India.
Department of Chemistry, DAV College, Sector 10, Chandigarh-160011, India.
Phys Chem Chem Phys. 2022 Sep 21;24(36):21975-21994. doi: 10.1039/d2cp02601e.
According to clinical studies, the development of Alzheimer's disease (AD) is linked to the abnormal aggregation of amyloid-β (Aβ) peptides into toxic soluble oligomers, protofibrils as well as mature fibrils. The most acceptable therapeutic strategy for the treatment of AD is to block the Aβ aggregation. Sun and co-workers have reported a decapeptide, D-enantiomeric RTHLVFFARK-NH (rk10), which acts as a potent inhibitor of Aβ aggregation and efficiently disaggregates pre-assembled Aβ fibrils. However, the inhibitory mechanism of rk10 against Aβ aggregation and disassembly of fibrils remains obscure. To investigate the inhibitory mechanism of rk10 against Aβ aggregation and disassembly of fibrils, molecular dynamics (MD) simulations have been performed in the present study. The molecular docking analysis using AutoDock Vina predicted favourable binding of rk10 with the N-terminal and central hydrophobic core (CHC) residues of Aβ monomer (-5.3 kcal mol), and with the residues of chain A of Aβ protofibril structure (-6.9 kcal mol). The MD simulations depicted higher structural stability of Aβ monomer in the presence of rk10. Notably, rk10 prevented the sampling of β-sheet rich structures of Aβ monomer by reducing the side-chain contacts between N-terminal and C-terminal residues of Aβ monomer. The per-residue binding free energy analysis highlighted the significant contribution of Phe19 and Glu22 of Aβ monomer in binding with rk10, which corroborate with the H NMR (nuclear magnetic resonance) spectra of Aβ monomer + rk10 complex that depicted a change in the chemical shifts of amide protons of Phe19 and Glu22. Further, rk10 destabilized the Aβ protofibril structure by lowering the number of interchain hydrogen bonds. The binding free energy analysis predicted lower binding affinity between Aβ protofibril chains in the presence of rk10 as compared to Aβ protofibril alone. The insights into the inhibitory mechanism of rk10 against Aβ aggregation and disassembly of fibrils will be beneficial for the design and development of potent anti-amyloid inhibitors.
根据临床研究，阿尔茨海默病（AD）的发展与淀粉样β（Aβ）肽异常聚集为有毒可溶性寡聚物、原纤维以及成熟纤维有关。治疗 AD 的最可接受的治疗策略是阻止 Aβ聚集。孙等人报道了一种十肽，D-对映体 RTHLVFFARK-NH（rk10），它可以作为 Aβ聚集的有效抑制剂，并有效地解聚预先组装的 Aβ纤维。然而，rk10 抑制 Aβ聚集和纤维解聚的机制仍不清楚。为了研究 rk10 抑制 Aβ聚集和纤维解聚的机制，本研究进行了分子动力学（MD）模拟。使用 AutoDock Vina 的分子对接分析预测 rk10 与 Aβ单体的 N 端和中央疏水区（CHC）残基（-5.3 kcal/mol）以及 Aβ原纤维结构的链 A 残基（-6.9 kcal/mol）具有良好的结合。MD 模拟表明 rk10 存在时 Aβ单体具有更高的结构稳定性。值得注意的是，rk10 通过减少 Aβ单体 N 端和 C 端残基之间的侧链接触，阻止了 Aβ单体富含β-折叠结构的采样。残基结合自由能分析突出了 Aβ单体中 Phe19 和 Glu22 残基在与 rk10 结合中的重要贡献，这与 Aβ单体+rk10 复合物的 NMR（核磁共振）谱一致，该谱表明 Phe19 和 Glu22 的酰胺质子的化学位移发生了变化。此外，rk10 通过降低链间氢键的数量使 Aβ原纤维结构失稳。结合自由能分析预测，与单独的 Aβ原纤维相比，rk10 存在时 Aβ原纤维链之间的结合亲和力较低。rk10 抑制 Aβ聚集和纤维解聚的机制的见解将有助于设计和开发有效的抗淀粉样抑制剂。
