Nanomedicine and protein misfolding diseases

Misfolding and self-assembly of proteins in nanoaggregates of different sizes and morphologies (nanoensembles, primarily nanofilaments and nanorings) is a complex phenomenon that can be facilitated, impeded, or prevented by interactions with various intracellular metabolites, intracellular nanomachines controlling protein folding, and interactions with other proteins. A fundamental understanding of molecular processes leading to misfolding and self-aggregation of proteins involved in various neurodegenerative diseases will provide important information to help identify appropriate therapeutic routes to control these processes. An elevated propensity of misfolded protein conformation in solution to aggregate with the formation of various morphologies impedes the use of traditional physiochemical approaches for studies of misfolded conformations of proteins. Here we tethered the protein molecules to surfaces to prevent aggregation and, with force spectroscopy using an atomic force microscopy, probed the interaction between protein molecules depending on their conformations. We show that formation of filamentous aggregates is facilitated at pH values corresponding to the maximum of rupture forces. We report here on development of a novel surface chemistry for anchoring of amyloid β (Aβ) peptides at their N-terminal moieties. The use of the site-specific immobilization procedure allowed us to measure the rupture of Aβ-Aβ contacts at the single-molecule level. The rupture of these contacts is accompanied by the extension of the peptide chain detected by a characteristic elastomechanical component of the force-distance curves. Potential applications of nanomechanical studies for understanding the mechanisms of development of protein misfolding diseases are discussed.