Tautomerization Effect of Histidines on Oligomer Aggregation of β‑Amyloid(1–40/42) during the Early Stage: Tautomerism Hypothesis for Misfolding Protein Aggregation

• Published in: ACS chemical neuroscience Vol. 10; no. 5; pp. 2602 - 2608
• Main Authors: Xing, Xiaofeng, Zhao, Wei, Hu, Dingkun, Kang, Baotao, Shi, Hu, Lee, Jin Yong, Ai, Hongqi
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 15.05.2019
• Subjects: Amyloid beta-Peptides - chemistry; Histidine - chemistry; Molecular Dynamics Simulation; Molecular Structure; Peptide Fragments - chemistry; Protein Aggregates - physiology; Protein Folding; Aβ40/42; hypothesis for AD; Tautomerization effect; oligomer aggregation; histidine
• ISSN: 1948-7193; 1948-7193
• DOI: 10.1021/acschemneuro.9b00094

As the intrinsic origin of the hypothesis for β-amyloid (Aβ) from Alzheimer’s disease, histidine behaviors were found to play a crucial role in Aβ aggregation. To investigate the histidine behaviors during the early stage of aggregation, Aβ40/42 pentamers with different histidine isomer states were simulated at the atomic level. Results show that five Aβ40 (δδδ) and Aβ42 (εδδ) monomers can rapidly decrease the aggregation threshold, promote stable pentamer formation, and increase pentamer contents by 51.8% and 56.7%, respectively, as compared with the values of their wild-type (εεε) counterparts. Additionally, pentamers of Aβ40 (δδδ) and Aβ42 (εδδ) have different aggregation pathways and disassembly species, Tr+D and Te+M, during the growth of the pentamer. This work discloses the significance of histidine tautomerization in Aβ aggregation, implying a potential way to control Aβ aggregation and develop the assembly inhibitors.