Surface-Induced Conformational Changes of α-Synuclein on Silica Nanoparticles of Varying Sizes Corresponding to...

Protein-nanoparticle interactions are crucial in a diverse array of biotechnology and biomedical applications. Variations in nanoparticle sizes can adjust surface interactions with proteins and biomolecules, thereby influencing their conformation and functionality. To achieve precise control over the nanoparticle sizes corresponding to the dimensions of protein structural domains (∼nm) and establish the relationship between nanoparticle curvature and protein conformational changes, we conduct well-tempered metadynamics simulations to explore the secondary structure changes and thermodynamic characteristics of α-synuclein (αS), an intrinsically disordered protein (IDP), adsorbed onto silicon dioxide (SiO₂) nanoparticles of varying sizes (diameter, d = 0.5-2.5 nm). The analysis of αS's conformational landscapes and structural probabilities reveals that intermediate-sized SiO₂ nanoparticles (d = 1.2-1.4 nm) effectively stabilize the native intrinsically disordered conformations of αS (with domain sizes of 1-2 nm). In contrast, excessively large or small SiO₂ nanoparticles significantly enhance the likelihood of forming intramolecular β-sheet domains within αS chains, a process that is critical for subsequent aggregation of αS. This study is of significance to the development of nanoparticles that stabilize desired protein conformations, which may pave the way for in vivo penetration and distribution of nanoparticles as well as biomedicine therapeutic interventions aimed at targeting αS aggregation.