Defining the Dynamic Conformational Networks of Cross-β Peptide Assembly

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Structurally defined cross-β assemblies have allowed for the development of basis sets for isotope-edited infrared spectra to follow progressive assembly over time. These basis sets, composed of a minimal number of individual spectra, are sufficient to identify the populations of polymorphs evolving throughout the assembly process. This approach provides, for the first time, the spectral assignment and relative distribution of paracrystalline intermediates formed from the intermolecular molten globule phase where nucleation occurs. Using the basis sets, we can now follow how subtle changes in assembly energetics impact the accessible polymorphs along the assembly pathway. Here, simple methylation of the Gln22 side chain of the nucleating core of the Dutch mutant of the Aβ of Alzheimer’s disease, Aβ(16-22)E22Q, dramatically increases the distribution of sampled polymorphs and slows progression to the final thermodynamic assembly. These data establish that amyloid cross-β structures can assemble through a dynamic conformational phylogeny. This fluid context-dependent network, so accessible to simple peptides, may provide the basis for the conformational selection and evolution of the complex supramolecular assemblies implicated in the many protein misfolding and prion diseases.


Copyright 2015 Wiley. A link has been provided to a presubmission pdf. Final Published article available http://onlinelibrary.wiley.com/doi/10.1002/ijch.201500012/abstract?

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Israel Journal of Chemistry

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Smith, J. E., Liang, C, Tseng, M., Li, N., Li, S., Mowles, A. K., Mehta, A. K., Lynn, D. G. Defining the Dynamic Conformational Networks of Cross-β Peptide Assembly. Israel Journal of Chemistry. June 2015, 55 (6-7), pp 763-769