Elucidation of factors for interspecific differences in alpha-synuclein amyloid aggregation using computational chemistry

2022 Fiscal Year Final Research Report

• Project/Area Number: 19K16058
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 43020:Structural biochemistry-related
• Research Institution: Nagasaki University
• Principal Investigator: OTAKI Hiroki 長崎大学, 医歯薬学総合研究科(医学系), 助教 (50632858)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Keywords: アミロイド / αシヌクレイン / 分子動力学計算 / 疎水性相互作用 / プリオン

Outline of Final Research Achievements

Abnormal accumulation of amyloids is observed in central nervous system of patients with neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and Prion diseases. It is well established that amyloid is predominantly composed of a β-sheet structure. However, how subtle differences in amino acid sequences between species affect the amyloid aggregation is still unclear. In this work, we analyzed the influence of different hydrophobic residues on the structures of an in-register parallel β-sheet amyloid of α-synuclein and a local structure of human PrPSc using molecular dynamics simulation. We found that mutations equivalent to polymorphisms that cause transmission barriers substantially affect the stability of the local structures. Our results indicate that subtle differences of hydrophobic interaction network can considerably affect the structures of in-register parallel β-sheet amyloid.

Free Research Field

生物物理

Academic Significance and Societal Importance of the Research Achievements

アミロイドは多くの神経変性疾患に関与している。アミノ酸配列の僅かな差異が凝集性に大きく影響する原因を明らかにすることは，構造生物学的な観点だけでなくアミロイドが関わる神経変性疾患の医学的な研究としても大きな意義がある。また，アミロイドの凝集性に関する理解が深まることにより，凝集を阻害する薬剤の開発など創薬分野への応用も期待される。