Bioinformatics Lab, Department of Biotechnology, School of Bio Sciences and Technology, VIT (Deemed to be University), Vellore, Tamil Nadu, 632014, India.
J Comput Aided Mol Des. 2018 Dec;32(12):1347-1361. doi: 10.1007/s10822-018-0175-1. Epub 2018 Oct 28.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that has been associated with mutations in metalloenzyme superoxide dismutase (SOD1) causing protein structural destabilization and aggregation. However, the mechanistic action and the cure for the disease still remain obscure. Herein, we initially studied the conformational preferences of SOD1 protein structures upon substitution of Ala at Gly93 in comparison with that of wild type. Our results corroborated with the previous experimental studies on the aggregation and the destabilizing activity of mutant SOD1 protein G93A. On the therapeutic point of view, we computationally analyzed the influence of resveratrol, a natural polyphenol widely found in red wine on mutant SOD1 relative to wild type, using molecular docking studies. Further, FMO calculations were performed, using GAMESS to study the pair residual interaction on the wild type and mutant complex systems. Consequently, the resveratrol showed greater interaction with mutant than the wild type. Subsequently, we evaluated the conformational preferences of wild type and mutant complex systems, where the protein conformational structures of mutant that were earlier found to lose their conformational stability was regained, upon binding with resveratrol. Similar trend of results were found on the 2-D free energy landscapes of both the wild type and mutant systems. Hence, the combined biophysical and quantum chemical studies in our study supported the results of previous experimental studies, thereby stipulating an action of resveratrol on mutant SOD1 and paving a way for the design of highly potent effective inhibitors against fALS affecting the mankind.
肌萎缩侧索硬化症（ALS）是一种神经退行性疾病，与金属酶超氧化物歧化酶（SOD1）的突变有关，这些突变导致蛋白质结构不稳定和聚集。然而，该疾病的发病机制和治疗方法仍然不清楚。在此，我们最初研究了在甘氨酸 93 位取代丙氨酸后 SOD1 蛋白质结构的构象偏好，与野生型进行比较。我们的结果与之前关于突变型 SOD1 G93A 蛋白聚集和不稳定活性的实验研究结果一致。从治疗的角度来看，我们使用分子对接研究，计算分析了白藜芦醇（一种在红酒中广泛存在的天然多酚）对突变型 SOD1 相对于野生型的影响。此外，使用 GAMESS 进行 FMO 计算，研究了野生型和突变复合物系统中对剩余相互作用的影响。结果表明，白藜芦醇与突变体的相互作用大于与野生型的相互作用。随后，我们评估了野生型和突变复合物系统的构象偏好，在与白藜芦醇结合后，先前发现失去构象稳定性的突变体的蛋白质构象结构得以恢复。在野生型和突变型系统的二维自由能景观中都发现了类似的结果趋势。因此，我们的研究中结合生物物理和量子化学的研究结果支持了先前实验研究的结果，从而规定了白藜芦醇对突变型 SOD1 的作用，并为设计针对影响人类的 fALS 的高效有效抑制剂铺平了道路。
