Santoro Angelo, Grimaldi Manuela, Buonocore Michela, Stillitano Ilaria, D'Ursi Anna Maria
Department of Pharmacy, University of Salerno, Via Giovanni Paolo II, 132-84084 Fisciano, SA, Italy.
Pharmaceuticals (Basel). 2021 Jul 27;14(8):732. doi: 10.3390/ph14080732.
Alzheimer's disease (AD) is a neurodegenerative pathology characterized by the presence of neurofibrillary tangles and amyloid plaques, the latter mainly composed of Aβ(1-40) and Aβ(1-42) peptides. The control of the Aβ aggregation process as a therapeutic strategy for AD has prompted the interest to investigate the conformation of the Aβ peptides, taking advantage of computational and experimental techniques. Mixtures composed of systematically different proportions of HFIP and water have been used to monitor, by NMR, the conformational transition of the Aβ(1-42) from soluble α-helical structure to β-sheet aggregates. In the previous studies, 50/50 HFIP/water proportion emerged as the solution condition where the first evident Aβ(1-42) conformational changes occur. In the hypothesis that this solvent reproduces the best condition to catch transitional helical-β-sheet Aβ(1-42) conformations, in this study, we report an extensive NMR conformational analysis of Aβ(1-42) in 50/50 HFIP/water /. Aβ(1-42) structure was solved by us, giving evidence that the evolution of Aβ(1-42) peptide from helical to the β-sheet may follow unexpected routes. Molecular dynamics simulations confirm that the structural model we calculated represents a starting condition for amyloid fibrils formation.
阿尔茨海默病（AD）是一种神经退行性病变，其特征为存在神经原纤维缠结和淀粉样斑块，后者主要由Aβ(1 - 40)和Aβ(1 - 42)肽组成。将控制Aβ聚集过程作为AD的一种治疗策略，这促使人们利用计算和实验技术来研究Aβ肽的构象。由不同比例的六氟异丙醇（HFIP）和水系统组成的混合物已被用于通过核磁共振（NMR）监测Aβ(1 - 42)从可溶性α - 螺旋结构到β - 折叠聚集体的构象转变。在先前的研究中，50/50的HFIP/水比例被认为是Aβ(1 - 42)首次出现明显构象变化的溶液条件。基于这种溶剂能再现捕捉螺旋 - β - 折叠过渡态Aβ(1 - 42)构象的最佳条件这一假设，在本研究中，我们报告了在50/50的HFIP/水体系中对Aβ(1 - 42)进行的广泛NMR构象分析。我们解析了Aβ(1 - 42)的结构，结果表明Aβ(1 - 42)肽从螺旋结构向β - 折叠结构的转变可能遵循意想不到的途径。分子动力学模拟证实，我们计算出的结构模型代表了淀粉样纤维形成的起始条件。
