Abstract：
Neuronal damage in iron-sensitive brain regions occurs as a result of iron dyshomeostasis. Increased iron levels and iron-related pathogenic triggers are associated with neurodegenerative diseases, including Alzheimer\'s disease (AD). Ferritin is a key player involved in iron homeostasis. Major pathological hallmarks of AD are amyloid plaques, neurofibrillary tangles (NFTs) and synaptic loss that lead to cognitive dysfunction and memory loss. Natural compounds persist in being the most excellent molecules in the area of drug discovery because of their different range of therapeutic applications. Bryostatins are naturally occurring macrocyclic lactones that can be implicated in AD therapeutics. Among them, Bryostatin 1 regulates protein kinase C, a crucial player in AD pathophysiology, thus highlighting the importance of bryostatin 1 in AD management. Thus, this study explores the binding mechanism of Bryotstain 1 with ferritin. In this work, the molecular docking calculations revealed that bryostatin 1 has an appreciable binding potential towards ferritin by forming stable hydrogen bonds (H-bonds). Molecular dynamics simulation studies deciphered the binding mechanism and conformational dynamics of ferrritin-bryostatin 1 system. The analyses of root mean square deviation, root mean square fluctuations, Rg, solvent accessible surface area, H-bonds and principal component analysis revealed the stability of the ferritin-bryostatin 1 docked complex throughout the trajectory of 100 ns. Moreover, the free energy landscape analysis advocated that the ferritin-bryostatin 1 complex stabilized to the global minimum. Altogether, the present work delineated the binding of bryostatin 1 with ferritin that can be implicated in the management of AD.Communicated by Ramaswamy H. Sarma.
摘要：
铁敏感脑区的神经元损伤是铁代谢异常的结果。铁水平升高和铁相关的致病触发因素与神经退行性疾病相关，包括阿尔茨海默病（AD）。铁蛋白是参与铁稳态的关键参与者。AD的主要病理标志是淀粉样蛋白斑,神经原纤维缠结（NFT）和突触丢失导致认知功能障碍和记忆丧失。天然化合物由于其不同的治疗应用范围而持续成为药物发现领域中最优异的分子。苔藓抑制素是天然存在的大环内酯,其可涉及AD治疗。其中,苔藓抑素1调节蛋白激酶C，AD病理生理学的关键参与者，从而突出苔藓抑素1在AD管理中的重要性。因此，本研究探讨了Bryotstain1与铁蛋白的结合机制。在这项工作中,分子对接计算表明苔藓抑素1通过形成稳定的氢键（H键）对铁蛋白具有明显的结合潜力。分子动力学模拟研究破译了铁蛋白-苔藓抑素1系统的结合机制和构象动力学。均方根偏差分析，均方根波动，Rg,溶剂可及表面积,H键和主成分分析揭示了铁蛋白-苔藓抑素1对接复合物在整个100ns轨迹中的稳定性。此外，自由能景观分析认为铁蛋白-苔藓抑素1复合物稳定到全球最低。总之,目前的工作描述了苔藓抑素1与铁蛋白的结合，这可能与AD的管理有关。由RamaswamyH.Sarma沟通。
