Inhibition of α-Synuclein Misfolding into β-Sheet Domains on Medium-Sized Gold Nanoclusters: Evidence from Enhanced Sampling MD Simulations.

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  • Author(s): Gong S;Gong S; Gao G; Gao G; Sun T; Sun T; Shen L; Shen L
  • Source:
    ACS macro letters [ACS Macro Lett] 2024 Nov 19; Vol. 13 (11), pp. 1476-1482. Date of Electronic Publication: 2024 Oct 22.
  • Publication Type:
    Journal Article
  • Language:
    English
  • Additional Information
    • Source:
      Publisher: American Chemical Society Country of Publication: United States NLM ID: 101574672 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2161-1653 (Electronic) Linking ISSN: 21611653 NLM ISO Abbreviation: ACS Macro Lett Subsets: MEDLINE
    • Publication Information:
      Original Publication: Washington, D.C. : American Chemical Society, [2012]-
    • Subject Terms:
      alpha-Synuclein*/metabolism ; alpha-Synuclein*/chemistry ; Gold*/chemistry ; Metal Nanoparticles*/chemistry ; Metal Nanoparticles*/therapeutic use ; Molecular Dynamics Simulation* ; Protein Folding*; Protein Conformation, beta-Strand ; Humans ; Parkinson Disease/drug therapy ; Parkinson Disease/metabolism ; Thermodynamics
    • Abstract:
      Targeting Parkinson's disease (PD) related protein, α-synuclein (αS), via gold nanoclusters (AuNCs) has received considerable attention in PD treatments, but its molecular basis on the initial interactions between αS and AuNCs remains elusive due to the absence of a unique secondary structure of αS chains. Here, at the single-cluster level, we incorporate well-tempered metadynamics simulations to explore the structural and thermodynamic characteristics of the full length αS adsorbed on different-sized AuNCs (Au n , n = 25, 36, 44, 68, 102) with modeled thiolated ligands (Au n @Lig). The conformational landscapes of αS indicate that uncharged Au n @SCH 2 OH chaperones the native intrinsically disordered conformations of αS, while negatively and positively charged AuNCs greatly increase the likelihood of forming intramolecular β-sheet domains, which are necessary for αS fibrillation and are a hallmark of PD. The binding details further demonstrate the significant inhibitory effect of the medium-sized Au 36 @SCH 2 OH on αS misfolding into β-sheet domains. This provides a valuable guideline for customizing AuNCs to precisely manipulate protein folding and misfolding behaviors, with potential implications for disease treatments.
    • Accession Number:
      0 (alpha-Synuclein)
      7440-57-5 (Gold)
    • Publication Date:
      Date Created: 20241022 Date Completed: 20241119 Latest Revision: 20241119
    • Publication Date:
      20241119
    • Accession Number:
      10.1021/acsmacrolett.4c00533
    • Accession Number:
      39437152