Division of Molecular Biosciences, Imperial College South Kensington Campus, London, SW7 2AZ, UK.
J Biomol Struct Dyn. 2013;31(5):441-52. doi: 10.1080/07391102.2012.703070. Epub 2012 Aug 9.
Human prion diseases are neurodegenerative disorders associated to the misfolding of the prion protein (PrP). Common features of prion disorders are the fibrillar amyloid deposits and the formation of prefibrillar oligomeric species also suggested as the origin of cytotoxicity associated with diseases. Although the process of PrP misfolding has been extensively investigated, many crucial aspects of this process remain unclear. We have here carried out a molecular dynamics study to evaluate the intrinsic dynamics of PrP β-sheet, a region that is believed to play a crucial role in prion aggregation. Moreover, as this region mediates protein association in dimeric assemblies frequently observed in prion crystallographic investigations, we also analyzed the dynamics of these intermolecular interactions. The extensive sampling of replica exchange shows that the native antiparallel β-structure of the prion is endowed with a remarkable stability. Therefore, upon unfolding, the persistence of a structured β-region may seed molecular association and influence the subsequent phases of the aggregation process. The analysis of the four-stranded β-sheet detected in the dimeric assemblies of PrP shows a tendency of this region to form dynamical structured states. The impact on the β-sheet structure and dynamics of disease associated point mutations has also been evaluated.
人类朊病毒病是与朊蛋白（PrP）错误折叠相关的神经退行性疾病。朊病毒疾病的共同特征是纤维状淀粉样沉积物和前纤维寡聚体的形成，也被认为是与疾病相关的细胞毒性的起源。尽管 PrP 错误折叠的过程已经被广泛研究，但这个过程的许多关键方面仍然不清楚。我们在这里进行了分子动力学研究，以评估 PrP β-折叠的固有动力学，该区域被认为在朊病毒聚集中起着至关重要的作用。此外，由于该区域介导了朊病毒晶体学研究中经常观察到的二聚体组装中的蛋白质缔合，我们还分析了这些分子间相互作用的动力学。广泛的复制交换采样表明，朊病毒的天然反平行β-结构具有显著的稳定性。因此，在展开时，结构化β-区域的持续存在可能会引发分子缔合，并影响聚集过程的后续阶段。对 PrP 二聚体组装中检测到的四股β-折叠的分析表明，该区域有形成动态结构状态的趋势。还评估了与疾病相关的点突变对β-折叠结构和动力学的影响。
