Stability and Structure of Amyloid-Forming Peptides from Computer Simulation

Proteins and peptides can fold into their unique 3-dimensional (3D) structures to perform their biological functions, or they can misfold to form insoluble amyloid fibrils, which are highly ordered protein aggregates currently known to be associated with more than 20 neurodegenerative diseases, including Alzheimer’s, Parkinson’s, Huntington’s, diabetes type II, and various prion diseases (1-4). Regardless of the differences in size, function, sequence, and native structures of these amyloid-forming proteins/peptides, all amyloid fibrils adopt a common cross-β-sheet structure, in which the β-sheets are parallel to the fibril axis and the β-strands within a sheet are perpendicular to the fibril axis. Moreover, recent experiments found that even those disease-unrelated proteins/peptides also have an intrinsic tendency to form highly ordered amyloid fibrils under appropriate conditions (5). These findings imply that a general principle may govern amyloid fibril formation (6). Most importantly, although fibril formation is linked to neurotoxicity, accumulating evidences point to soluble oligomeric intermediates, rather than insoluble fibrils, as the primary toxic species (7-9), possibly due to their membrane-disruption abilities, while mature fibrils may represent an inert monomer reservoir. Amyloid oligomers are directly linked to infectivity as well arising from the instability of fibrils (10, 11) -the higher tendency of the fibrils to break into oligomers, the more infection they are. Additionally, these prefibrillar intermediates display various discrete morphologies (micelle-like, annular-like, and linear-like structures) as observed by atomic force microscopy (AFM) and electron microscopy (EM) when exposed to different environmental conditions (1214), suggesting that fibrillization/oligomerization may proceed through multiple assembly pathways. Despite substantial efforts and progresses have been made, the mechanism of amyloid formation and the origin of its toxicity are still not fully understood, primarily because little was known until recently about the molecular-level structures of fibrils, apart from the existence of the cross-β motif (15).