Insights into stability and toxicity of amyloid-like oligomers by replica exchange molecular dynamics analyses.
Deposition of insoluble amyloid plaques is frequently associated with a large variety of neurodegenerative diseases. However, data collected in the last decade have suggested that the neurotoxic action is exerted by prefibrillar, soluble assemblies of amyloid-forming proteins and peptides. The scarcity of structural data available for both amyloid-like fibrils and soluble oligomers is a major limitation for the definition of the molecular mechanisms linked to the onset of these diseases. Recently, the structural characterization of GNNQQNY and other peptides has shown a general feature of amyloid-like fibers, the so-called steric zipper motif. However, very little is known still about the prefibrillar oligomeric forms. By using replica exchange molecular dynamics we carried out extensive analyses of the properties of several small and medium GNNQQNY aggregates arranged through the steric zipper motif. Our data show that the assembly formed by two sheets, each made of two strands, arranged as in the crystalline states are highly unstable. Conformational free energy surfaces indicate that the instability of the model can be ascribed to the high reactivity of edge backbone hydrogen bonding donors/acceptors. On the other hand, data on larger models show that steric zipper interactions may keep small oligomeric forms in a stable state. These models simultaneously display two peculiar structural motifs: a tightly packed steric zipper interface and a large number of potentially reactive exposed strands. The presence of highly reactive groups on these assemblies likely generates two distinct evolutions. On one side the reactive groups quickly lead, through self-association, to the formation of ordered fibrils, on the other they may interfere with several cellular components thereby generating toxic effects. In this scenario, fiber formation propensity and toxicity of oligomeric states are two different manifestations of the same property: the hyper-reactivity of the exposed strands.
De Simone
Alfonso
A
Istituto di Biostrutture e Bioimmagini, CNR, and Dipartimento delle Scienze Biologiche, Università Federico II, I-80134 Naples, Italy. ad491@cam.ac.uk
Esposito
Luciana
L
Pedone
Carlo
C
Vitagliano
Luigi
L
D000682:Amyloid / Q000737:chemistry* / Q000633:toxicity / Q000648:ultrastructure*; D003198:Computer Simulation; D008956:Models, Chemical; D008958:Models, Molecular; D046912:Multiprotein Complexes / Q000737:chemistry* / Q000633:toxicity / Q000648:ultrastructure*; D011487:Protein Conformation; D011489:Protein Denaturation
D000682:Amyloid; D046912:Multiprotein Complexes