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

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@SCH₂OH 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 Au₃₆@SCH₂OH 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.