Isomeric Effect of Nano-Inhibitors on Aβ40 Fibrillation at The Nano-Bio Interface

Chemical and physical properties of nanobio interface substantially affect the conformational transitions of adjacent biomolecules. Previous studies have reported the chiral effect and charge effect of nanobio interface on the misfolding, aggregation, and fibrillation of amyloid protein. However, the isomeric effect of nanobio interface on protein/peptides amyloidosis is still unclear. Here, three isomeric nanobio interfaces were designed and fabricated based on the same sized gold nanoclusters (AuNCs) modified with 4-mercaptobenzoic acid (p-MBA), 3-mercaptobenzoic acid (m-MBA), and 2-mercaptobenzoic acid (o-MBA). Then three isomeric AuNCs were employed as models to explore the isomeric effect on the misfolding, aggregation, and fibrillation of A beta(40) at nanobio interfaces. Site-specific replacement experiments on the basis of theoretical analysis revealed the possible mechanism of A beta(40) interacting with isomeric ligands of AuNCs at the nanobio interfaces. The distance and orientation of -COOH group from the surface of AuNCs can affect the electrostatic interaction between isomeric ligands and the positively charged residues (R5, K16, and K28) of A beta(40), which may affect the inhibition efficiency of isomeric AuNCs on protein amyloidosis. Actually, the amyloid fibrillation kinetics results together with atomic force microscope (AFM) images, dynamic light scattering (DLS) results and circular dichroism (CD) spectra indeed proved that all the three isomeric AuNCs could inhibit the misfolding, aggregation and fibrillation of A beta(40) in a dose-dependent manner, and the inhibition efficiency was definitely different from each other. The inhibition efficiency of o-MBA-AuNCs was higher than that of m-MBA-AuNCs and p-MBA-AuNCs at the same dosage. These results provide an insight for isomeric effect at nanobio interfaces, and open an avenue for structure-based nanodrug design target Alzheimer's disease (AD) and even other protein conformational diseases.

Automated summary

The chemical and physical properties of nanobio interfaces can significantly impact the conformational transitions of adjacent biomolecules. This study investigates the isomeric effect of nanobio interfaces on the misfolding, aggregation, and fibrillation of A beta(40) using three different isomeric AuNCs. The results show that the inhibition efficiency of o-MBA-AuNCs is higher than that of m-MBA-AuNCs and p-MBA-AuNCs, providing insights for structure-based nanodrug design targeting Alzheimer's disease and other protein conformational diseases.