Simulating the anti-aggregative effect of fasudil in early dimerisation process of α-synuclein.
Biophys Chem
; 314: 107319, 2024 Nov.
Article
em En
| MEDLINE
| ID: mdl-39232485
ABSTRACT
The aggregation of the protein α-synuclein into amyloid deposits is associated with multiple neurological disorders, including Parkinson's disease. Soluble amyloid oligomers are reported to exhibit higher toxicity than insoluble amyloid fibrils, with dimers being the smallest toxic oligomer. Small molecule drugs, such as fasudil, have shown potential in targeting α-synuclein aggregation and reducing its toxicity. In this study, we use atomistic molecular dynamics simulations to demonstrate how fasudil affects the earliest stage of aggregation, namely dimerization. Our results show that the presence of fasudil reduces the propensity for intermolecular contact formation between protein chains. Consistent with previous reports, our analysis confirms that fasudil predominantly interacts with the negatively charged C-terminal region of α-synuclein. However, we also observe transient interactions with residues in the charged N-terminal and hydrophobic NAC regions. Our simulations indicate that while fasudil prominently interacts with the C-terminal region, it is the transient interactions with residues in the N-terminal and NAC regions that effectively block the formation of intermolecular contacts between protein chains and prevent early dimerization of this disordered protein.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
1-(5-Isoquinolinasulfonil)-2-Metilpiperazina
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Alfa-Sinucleína
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Multimerização Proteica
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Simulação de Dinâmica Molecular
Limite:
Humans
Idioma:
En
Revista:
Biophys Chem
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
Índia
País de publicação:
Holanda