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Originally published as Biophys J. BioFAST on February 9, 2007.
doi:10.1529/biophysj.106.100404
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Biophysical Journal 92:3032-3039 (2007)
© 2007 The Biophysical Society

Structure and Dynamics of Parallel ß-Sheets, Hydrophobic Core, and Loops in Alzheimer's Aß Fibrils

Nicolae-Viorel Buchete and Gerhard Hummer

Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-0520

Correspondence: Address reprint requests to G. Hummer, Tel.: 301-402-6290; E-mail: hummer{at}helix.nih.gov or gerhard.hummer{at}nih.gov.

We explore the relative contributions of different structural elements to the stability of Aß fibrils by molecular-dynamics simulations performed over a broad range of temperatures (298 K to 398 K). Our fibril structures are based on solid-state nuclear magnetic resonance experiments of Aß(1–40) peptides, with sheets of parallel ß-strands connected by loops and stabilized by interior salt bridges. We consider models with different interpeptide interfaces, and different staggering of the N- and C-terminal ß-strands along the fibril axis. Multiple 10–20 ns molecular-dynamics simulations show that fibril segments with 12 peptides are stable at ambient temperature. The different models converge toward an interdigitated side-chain packing, and present water channels solvating the interior D23/K28 salt bridges. At elevated temperatures, we observe the early phases of fibril dissociation as a loss of order in the hydrophilic loops connecting the two ß-strands, and in the solvent-exposed N-terminal ß-sheets. As the most dramatic structural change, we observe collective sliding of the N- and C-terminal ß-sheets on top of each other. The interior C-terminal ß-sheets in the hydrophobic core remain largely intact, indicating that their formation and stability is crucial to the dissociation/elongation and stability of Aß fibrils.




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