Molecular Mechanisms of Misfolding of Amyloid Peptides

Abstract

The current model for the development of Alzheimer's, Parkinson's, Huntington's, prion, and other neurodegenerative diseases involves protein misfolding as the early step followed by spontaneous aggregation, with specific proteins identified as the primary initiators for disease development. Therefore, elucidating the properties of the disease-prone misfolded states, understanding the mechanism of their formation, and identification of their most toxic forms will open prospects for the development of early diagnostics and specific therapeutics for these diseases. We have developed single molecule AFM force spectroscopy (SMFS) experimental approach enabling us to probe interprotein interactions and to identify those interactions that correspond to misfolded protein states. Using SMFS, we have discovered that the misfolded dimers are very stable and have a lifetime in a second time scale. Such a long lifetime of dimers suggests that the formation of dimers is the mechanism by which the protein misfolded state is stabilized. We hypothesize that the formation of highly stable misfolded dimers is a critical step in the entire process of the peptide self-assembly into aggregates. The Molecular Dynamics (MD) simulation performed at the μs timescale demonstrated that isolated non-structured monomer upon approaching to each other changed dramatically their initial conformation and formed dimers with antiparallel beta-sheet structures. Steered MD approach showed that the dimers dissociated cooperatively resulting in a sharp rupture peak corresponding to breakage of the beta-sheet structure. Altogether, the SMFS experimental study and computational analysis revealed a critical role of the interpetide interaction in the misfolding process and highlighting the key role of the dimerization in the amyloid aggregation process. Acknowledgements: Grants from NIH (5R01 GM096039-02) and NSF (EPS-1004094).