Computational Chemistry Research Group, Ton Duc Thang University , Ho Chi Minh City, Vietnam.
Faculty of Applied Sciences, Ton Duc Thang University , Ho Chi Minh City, Vietnam.
J Phys Chem B. 2017 Sep 14;121(36):8467-8474. doi: 10.1021/acs.jpcb.7b05906. Epub 2017 Aug 30.
Familial Alzheimer's disease (FAD) is passed down in family, which account for 2-3% of about 40 million AD cases worldwide. The Flemish (A21G) mutant of amyloid β (Aβ) exhibits unique properties among all hereditary mutants of FAD, including the lowest aggregation rate. Recent studies showed that Aβ oligomers play a key role in Alzheimer's disease (AD) pathogenesis. They could insert themselves in brain cell membrane, disrupting the membrane integrity and ion homeostasis. However, experimental studies of transmembrane Aβ oligomers have been limited due to their intrinsic heterogeneity. In this work, we extensively studied the A21G mutant of the transmembrane 3Aβ (A21G 3Aβ) using temperature replica exchange molecular dynamics (REMD) simulations. Results provide detailed information on the conformational distribution and dynamics of transmembrane A21G 3Aβ. Minimal local change from A to G leads to significant conformational changes and wider free energy holes on the free energy surface as well as altered surface charges that lead to weaker affinity to the dipalmitoylphosphatidylcholine (DPPC) lipid bilayers. These results are consistent with experimental data that showed that A21G mutants of Aβ peptides have lower aggregation rates and membrane binding rates.
家族性阿尔茨海默病（FAD）在家族中遗传，占全球约 4000 万例 AD 病例的 2-3%。淀粉样蛋白β（Aβ）的弗拉芒（A21G）突变体在所有 FAD 的遗传性突变体中表现出独特的性质，包括最低的聚集率。最近的研究表明，Aβ寡聚物在阿尔茨海默病（AD）发病机制中起关键作用。它们可以插入脑细胞的细胞膜，破坏膜的完整性和离子动态平衡。然而，由于其内在的异质性，跨膜 Aβ寡聚物的实验研究受到限制。在这项工作中，我们使用温度复制交换分子动力学（REMD）模拟对跨膜 3Aβ 的 A21G 突变体（A21G 3Aβ）进行了广泛的研究。结果提供了关于跨膜 A21G 3Aβ构象分布和动力学的详细信息。从 A 到 G 的最小局部变化导致构象变化显著，自由能表面上的自由能孔变宽，表面电荷改变，导致与二棕榈酰磷脂酰胆碱（DPPC）脂质双层的亲和力降低。这些结果与实验数据一致，表明 Aβ肽的 A21G 突变体具有更低的聚集率和膜结合率。
