Vaccine and Infectious Disease Organization (VIDO), University of Saskatchewan, Saskatoon, SK, S7N 5E3, Canada.
Department of Physics, University of Kurdistan, P.O. Box 416, Sanandaj, Iran.
Sci Rep. 2023 Nov 3;13(1):19020. doi: 10.1038/s41598-023-46181-1.
Protein misfolding and aggregation play crucial roles in amyloidogenic diseases through the self-assembly of intrinsically disordered proteins (IDPs) in type II diabetes (T2D), Alzheimer's disease (AD) and Parkinson's disease (PD). PD is the most common neurodegenerative disorder after AD, and is associated with the loss of dopaminergic signaling, which causes motor and nonmotor signs and symptoms. Lewy bodies and Lewy neurites are common pathological hallmarks of PD that are mainly composed of aggregates of disordered α-synuclein (α-Syn). There have been many efforts to develop chemical compounds to prevent aggregation or facilitate disruption of the aggregates. Furthermore, the roles and interactions of many compounds have yet to be revealed at the atomistic level, especially their impacts on the dynamics and chain-chain interactions of the oligomers, which are of interest in this study. The conformational diversity and detailed interactions among homo-oligomer chains of α-Syn are not fully discovered; identifying these might help uncover a practical approach to developing a potent therapy. In this study, we used an in-silico investigation to address the conformational diversity of α-Syn oligomer. The roles of several point mutations in protein aggregation in PD are known; we take this further by evaluating the interaction energies and contributions of all residues in stability and residue-chain interactions. In this study, we docked chemical derivatives of three compounds with high drug-likeness properties to evaluate the roles of our ligands in the conformational dynamicity of the oligomers, with emphasis on intramolecular forces. Free energy evaluation of the modeled inter and intramolecular interactions through MD simulation shows effective interaction and binding between α-Syn and our compounds. However, we find that they do not significantly disrupt the chain-chain interactions, compared to unliganded simulation.
蛋白质错误折叠和聚集通过 II 型糖尿病 (T2D)、阿尔茨海默病 (AD) 和帕金森病 (PD) 中无规卷曲蛋白质 (IDP) 的自组装在淀粉样变性疾病中发挥关键作用。PD 是 AD 之后最常见的神经退行性疾病，与多巴胺能信号的丧失有关，导致运动和非运动症状和体征。路易体和路易神经突是 PD 的常见病理标志物，主要由无序α-突触核蛋白 (α-Syn) 的聚集物组成。已经有许多努力来开发化学化合物以防止聚集或促进聚集物的破坏。此外，许多化合物的作用和相互作用尚未在原子水平上揭示，特别是它们对低聚物动力学和链间相互作用的影响，这是本研究关注的焦点。α-Syn 同源寡聚物链之间的构象多样性和详细相互作用尚未完全发现；确定这些可能有助于揭示开发有效疗法的实际方法。在这项研究中，我们使用计算机模拟来解决α-Syn 低聚物的构象多样性问题。已知 PD 中几种点突变在蛋白质聚集中的作用；我们通过评估所有残基在稳定性和残基链相互作用中的相互作用能和贡献来进一步研究。在这项研究中，我们对接了三种具有高药物相似性特性的化学衍生物，以评估我们的配体在寡聚物构象动态性中的作用，重点是分子内力。通过 MD 模拟对建模的分子间和分子内相互作用进行自由能评估表明，α-Syn 与我们的化合物之间存在有效相互作用和结合。然而，与未配体模拟相比，我们发现它们并没有显著破坏链间相互作用。
