Hashemi Mohtadin, Lyubchenko Yuri L
Department of Pharmaceutical Science, University of Nebraska Medical Center, 986025 Nebraska Medical Center, Omaha, NE 68198-6025, United States.
Department of Pharmaceutical Science, University of Nebraska Medical Center, 986025 Nebraska Medical Center, Omaha, NE 68198-6025, United States.
Methods. 2022 Jan;197:89-96. doi: 10.1016/j.ymeth.2021.03.005. Epub 2021 Mar 13.
A broad range of human diseases, including Alzheimer's and Parkinson's diseases, arise from or have as key players intrinsically disordered proteins. The aggregation of these amyloid proteins into fibrillar aggregates are the key events of such diseases. Characterizing the conformation dynamics of the proteins involved is crucial for understanding the molecular mechanisms of aggregation, which in turn is important for drug development efforts against these diseases. Computational approaches have provided extensive detail about some steps of the aggregation process, however the biologically relevant elements responsible for the aggregation and or aggregation propagation have not been fully characterized. Here we describe a hybrid resolution molecular dynamics simulation method that can be employed to investigate the interaction of amyloid proteins with lipid membranes, shown to dramatically accelerate the aggregation propensity of amyloid proteins. The hybrid resolution method enables routine and accurate simulation of multi-protein and complex membrane systems, mimicking biologically relevant lipid membranes, on microsecond time scales. The hybrid resolution method was applied to computer modeling of the interactions of α -synuclein protein with a mixed lipid bilayer.
包括阿尔茨海默病和帕金森病在内的多种人类疾病都源于内在无序蛋白质或其在其中起关键作用。这些淀粉样蛋白聚集成纤维状聚集体是此类疾病的关键事件。表征相关蛋白质的构象动力学对于理解聚集的分子机制至关重要，而这反过来对于针对这些疾病的药物开发也很重要。计算方法已经提供了关于聚集过程某些步骤的大量细节，然而，负责聚集和/或聚集传播的生物学相关元素尚未得到充分表征。在这里，我们描述了一种混合分辨率分子动力学模拟方法，该方法可用于研究淀粉样蛋白与脂质膜的相互作用，结果表明脂质膜可显著加速淀粉样蛋白的聚集倾向。这种混合分辨率方法能够在微秒时间尺度上对多蛋白和复杂膜系统进行常规且准确的模拟，模拟具有生物学相关性的脂质膜。该混合分辨率方法被应用于α-突触核蛋白与混合脂质双层相互作用的计算机建模。
