Decoding the Roles of Amyloid-β (1-42)’s Key Oligomerization Domains toward Designing Epitope-Specific Aggregation Inhibitors

Dongjoon Im, Soohyeong Kim, Gyusub Yoon, Da Gyeong Hyun, Yu Gon Eom, Ye Eun Lee, Chang Ho Sohn, Jeong Mo Choi, Hugh I. Kim

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)


Fibrillar amyloid aggregates are the pathological hallmarks of multiple neurodegenerative diseases. The amyloid-β (1-42) protein, in particular, is a major component of senile plaques in the brains of patients with Alzheimer’s disease and a primary target for disease treatment. Determining the essential domains of amyloid-β (1-42) that facilitate its oligomerization is critical for the development of aggregation inhibitors as potential therapeutic agents. In this study, we identified three key hydrophobic sites (17LVF1932IGL34, and 41IA42) on amyloid-β (1-42) and investigated their involvement in the self-assembly process of the protein. Based on these findings, we designed candidate inhibitor peptides of amyloid-β (1-42) aggregation. Using the designed peptides, we characterized the roles of the three hydrophobic regions during amyloid-β (1-42) fibrillar aggregation and monitored the consequent effects on its aggregation property and structural conversion. Furthermore, we used an amyloid-β (1-42) double point mutant (I41N/A42N) to examine the interactions between the two C-terminal end residues with the two hydrophobic regions and their roles in amyloid self-assembly. Our results indicate that interchain interactions in the central hydrophobic region (17LVF19) of amyloid-β (1-42) are important for fibrillar aggregation, and its interaction with other domains is associated with the accessibility of the central hydrophobic region for initiating the oligomerization process. Our study provides mechanistic insights into the self-assembly of amyloid-β (1-42) and highlights key structural domains that facilitate this process. Our results can be further applied toward improving the rational design of candidate amyloid-β (1-42) aggregation inhibitors.

Original languageEnglish
Pages (from-to)1065-1075
Number of pages11
JournalJACS Au
Issue number4
Publication statusPublished - 2023 Apr 24

Bibliographical note

Funding Information:
This research was supported by a National Research Foundation (NRF) grant, funded by the Korean government (MSIT) (2019R1A2C2086193 and 2021R1A4A1032114 to H.I.K., 2021R1C1C1010943 and 2022R1A4A1033471 to J.-M.C., and 2021R1C1C1004092 and 2021H1D3A2A02096517 to C.H.S.), as well as the Korea Basic Science Institute (KBSI), National Research Facilities & Equipment Center (NFEC), funded by the Korean government (Ministry of Education) (2019R1A6C1010028, and 2020R1A6C103A027 to H.I.K.), and the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI) and Korea Dementia Research Center (KDRC), funded by the Ministry of Health & Welfare, Ministry of Science and ICT, Republic of Korea (grant number: HU21C0071 to H.I.K.) and Institute for Basic Science (IBS-R026-D1 to C.H.S.). Synchrotron X-ray scattering measurements at the 4C SAXS II beamline of the Pohang Accelerator Laboratory were supported by the Ministry of Education and Science Technology of Korea. This work was also supported by the National Institute of Supercomputing and Network/Korea Institute of Science and Technology Information with supercomputing resources, including technical support (KSC-2021-RND-0060 and KSC-2022-CRE-0341). The authors thank the National Center for Seoul National University Research Facilities for their assistance with the TEM measurements.

Publisher Copyright:
© 2023 The Authors. Published by American Chemical Society.


  • aggregation
  • conformation
  • inhibitors
  • oligomers
  • peptides and proteins

ASJC Scopus subject areas

  • Chemistry (miscellaneous)
  • Analytical Chemistry
  • Organic Chemistry
  • Physical and Theoretical Chemistry


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