School of Physical Science and Technology, Ningbo University, Ningbo 315211, China.
Department of Physics and Astronomy, Clemson University, Clemson, South Carolina 29634, United States.
J Phys Chem B. 2020 Nov 12;124(45):10138-10146. doi: 10.1021/acs.jpcb.0c07256. Epub 2020 Oct 29.
Inhibiting the cytotoxicity of amyloid aggregation by endogenous proteins is a promising strategy against degenerative amyloid diseases due to their intrinsically high biocompatibility and low immunogenicity. In this study, we investigated the inhibition mechanism of the structured core region of αB-crystallin (αBC) against Aβ fibrillization using discrete molecular dynamics simulations. Our computational results recapitulated the experimentally observed Aβ binding sites in αBC and suggested that αBC could bind to various Aβ aggregate species during the aggregation process-including monomers, dimers, and likely other high molecular weight oligomers, protofibrils, and fibrils-by capping the exposed β-sheet elongation surfaces. Thus, the nucleation of Aβ oligomers into fibrils and the fibril growth could be inhibited. Mechanistic insights obtained from our systematic computational studies may aid in the development of novel therapeutic strategies to modulate the aggregation of pathological, amyloidogenic protein in degenerative diseases.
内源性蛋白质抑制淀粉样聚集的细胞毒性是一种有前途的策略，可对抗退行性淀粉样疾病，因为它们具有固有高生物相容性和低免疫原性。在这项研究中，我们使用离散分子动力学模拟研究了 αB-晶状体蛋白 (αBC) 的结构化核心区域对 Aβ 纤维化的抑制机制。我们的计算结果再现了实验观察到的 αBC 中的 Aβ 结合位点，并表明 αBC 可以在聚集过程中结合各种 Aβ 聚集物，包括单体、二聚体以及可能的其他高分子量寡聚物、原纤维和纤维，通过覆盖暴露的β-片层延伸表面。因此，可以抑制 Aβ 寡聚物成核为纤维和纤维生长。我们系统的计算研究获得的机制见解可能有助于开发新的治疗策略，以调节退行性疾病中病理性、淀粉样蛋白的聚集。
