Dynamic molecular exchange and conformational transitions of alpha-synuclein at the nano-bio interface

The notion that nanoscale surfaces influence protein conformational transitions stimulates the investigation of fibrillogenic polypeptides adsorbing to nanomaterials. Alpha-synuclein (alpha S) is a prototypical amyloidogenic protein whose aggregation is associated with severe neurodegenerative disorders. We explored the interaction of alpha S with silica nanoparticles (SNPs) in diverse solution conditions, ranging from protein-free to protein-rich media. We found that the SNP-binding region of alpha S, determined by site-resolved NMR spectroscopy, was similar in simple buffer and blood serum. Competition binding experiments with isotopic homologues and different proteins showed that cosolutes elicited molecular exchange in a protein-specific manner. The interaction of an oxidized, fibrillation-resistant protein form with SNPs was similar to that of unmodified alpha S. SNPs, however, did not stimulate fibrillation of the oxidized protein, which remained fibrillation incompetent. CD experiments revealed SNP-induced perturbations of the structural properties of oxidized and non-oxidized alpha S. Thus, while alpha S binding to SNPs is essentially orthogonal to fibril formation, the interaction perturbs the distribution of conformational states populated by the protein in the colloidal suspension. This study sheds light on the dynamic nature of alpha S interactions with NPs, an aspect that crucially impacts on our ability to control aggregation of alpha S. (C) 2020 Elsevier B.V. All rights reserved.