Department of Chemistry, National Taiwan University, No. 1, Section 4, Roosevelt Road, Taipei, 10617, Taiwan.
Instrumentation Center, National Taiwan University, No. 1, Section 4, Roosevelt Road, Taipei, 10617, Taiwan.
Chemistry. 2023 Oct 18;29(58):e202301879. doi: 10.1002/chem.202301879. Epub 2023 Sep 14.
The underlying biophysical principle governing the cytotoxicity of the oligomeric aggregates of β-amyloid (Aβ) peptides has long been an enigma. Here we show that the size of Aβ oligomers can be actively controlled by incubating the peptides in reverse micelles. Our approach allowed for the first time a detailed comparison of the structures and dynamics of two Aβ oligomers of different sizes, viz., 10 and 23 nm, by solid-state NMR. From the chemical shift data, we infer that the conformation and/or the chemical environments of the residues from K16 to K28 are different between the 10-nm and 23-nm oligomers. We find that the 10-nm oligomers are more cytotoxic, and the molecular motion of the sidechain of its charged residue K16 is more dynamic. Interestingly, the residue A21 exhibits unusually high structural rigidity. Our data raise an interesting possibility that the cytotoxicity of Aβ oligomers could also be correlated to the motional dynamics of the sidechains.
长期以来，β-淀粉样蛋白 (Aβ) 肽寡聚体细胞毒性的潜在生物物理原理一直是个谜。在这里，我们表明通过在反胶束中孵育肽，可以主动控制 Aβ 寡聚体的大小。我们的方法首次允许通过固态 NMR 对两种不同大小（即 10nm 和 23nm）的 Aβ 寡聚体的结构和动态进行详细比较。根据化学位移数据，我们推断 10nm 和 23nm 寡聚体之间残基 K16 到 K28 的构象和/或化学环境不同。我们发现 10nm 寡聚体的细胞毒性更高，其带电荷残基 K16 的侧链分子运动更具动态性。有趣的是，残基 A21 表现出异常高的结构刚性。我们的数据提出了一个有趣的可能性，即 Aβ 寡聚体的细胞毒性也可能与侧链的运动动力学相关。
