3 years ago

Major Reaction Coordinates Linking Transient Amyloid-β Oligomers to Fibrils Measured at Atomic Level

Major Reaction Coordinates Linking Transient Amyloid-β Oligomers to Fibrils Measured at Atomic Level
Bappaditya Chandra, Kaustubh R. Mote, Barun Kumar Maity, Sudipta Maiti, Perunthiruthy K. Madhu, Debabrata Dhara, Debanjan Bhowmik, Ravindra Venkatramani


The structural underpinnings for the higher toxicity of the oligomeric intermediates of amyloidogenic peptides, compared to the mature fibrils, remain unknown at present. The transient nature and heterogeneity of the oligomers make it difficult to follow their structure. Here, using vibrational and solid-state nuclear magnetic resonance spectroscopy, and molecular dynamics simulations, we show that freely aggregating Aβ40 oligomers in physiological solutions have an intramolecular antiparallel configuration that is distinct from the intermolecular parallel β-sheet structure observed in mature fibrils. The intramolecular hydrogen-bonding network flips nearly 90°, and the two β-strands of each monomeric unit move apart, to give rise to the well-known intermolecular in-register parallel β-sheet structure in the mature fibrils. Solid-state nuclear magnetic resonance distance measurements capture the interstrand separation within monomer units during the transition from the oligomer to the fibril form. We further find that the D23–K28 salt-bridge, a major feature of the Aβ40 fibrils and a focal point of mutations linked to early onset Alzheimer's disease, is not detectable in the small oligomers. Molecular dynamics simulations capture the correlation between changes in the D23–K28 distance and the flipping of the monomer secondary structure between antiparallel and parallel β-sheet architectures. Overall, we propose interstrand separation and salt-bridge formation as key reaction coordinates describing the structural transition of the small Aβ40 oligomers to fibrils.

Publisher URL: http://www.cell.com/biophysj/fulltext/S0006-3495(17)30789-0

DOI: 10.1016/j.bpj.2017.06.068

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