Nanomechanics and intermolecular forces of amyloid revealed by four-dimensional electron microscopy
The amyloid state of polypeptides is a stable, highly organized structural form consisting of laterally associated β-sheet protofilaments that may be adopted as an alternative to the functional, native state. Identifying the balance of forces stabilizing amyloid is fundamental to understanding the wide accessibility of this state to peptides and proteins with unrelated primary sequences, various chain lengths, and widely differing native structures. Here, we use four-dimensional electron microscopy to demonstrate that the forces acting to stabilize amyloid at the atomic level are highly anisotropic, that an optimized interbackbone hydrogen-bonding network within β-sheets confers 20 times more rigidity on the structure than sequence-specific sidechain interactions between sheets, and that electrostatic attraction of protofilaments is only slightly stronger than these weak amphiphilic interactions. The potential biological relevance of the deposition of such a highly anisotropic biomaterial in vivo is discussed.
Additional Information© 2015 National Academy of Sciences. Contributed by Ahmed H. Zewail, February 3, 2015 (sent for review January 15, 2015). Published ahead of print March 2, 2015. This work was supported by the National Science Foundation (DMR-0964886) and the Air Force Office of Scientific Research (FA9550-11-1-0055) in the Gordon and Betty Moore Center for Physical Biology at the California Institute of Technology. A.W.P.F. is supported by a Marie Curie International Outgoing Fellowship. Author contributions: A.W.P.F., G.M.V., and A.H.Z. designed research, performed research, contributed new reagents/analytic tools, analyzed data, and wrote the paper. This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1502214112/-/DCSupplemental.
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Supplemental Material - pnas.201502214SI.pdf