Role of water in mediating the assembly of alzheimer amyloid-β Aβ16-22 protofilaments

Mary Griffin Krone, Lan Hua, Patricia Soto, Ruhong Zhou, B. J. Berne, Joan Emma Shea

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Abstract

The role of water in promoting the formation of protofilaments (the basic building blocks of amyloid fibrils) is investigated using fully atomic molecular dynamics simulations. Our model protofilament consists of two parallel β-sheets of Alzheimer Amyloid-β 16-22 peptides (Ac-K 16-L17-V18-F19-F20-A 21-E22-NH2). Each sheet presents a distinct hydrophobic and hydrophilic face and together self-assemble to a stable protofilament with a core consisting of purely hydrophobic residues (L 17, F19, A21), with the two charged residues (K16, E22) pointing to the solvent. Our simulations reveal a subtle interplay between a water mediated assembly and one driven by favorable energetic interactions between specific residues forming the interior of the protofilament. A dewetting transition, in which water expulsion precedes hydrophobic collapse, is observed for some, but not all molecular dynamics trajectories. In the trajectories in which no dewetting is observed, water expulsion and hydrophobic collapse occur simultaneously, with protofilament assembly driven by direct interactions between the hydrophobic side chains of the peptides (particularly between F-F residues). For those same trajectories, a small increase in the temperature of the simulation (on the order of 20 K) or a modest reduction in the peptide-water van der Waals attraction (on the order of 10%) is sufficient to induce a dewetting transition, suggesting that the existence of a dewetting transition in simulation might be sensitive to the details of the force field parametrization.

Original languageEnglish
Pages (from-to)11066-11072
Number of pages7
JournalJournal of the American Chemical Society
Volume130
Issue number33
DOIs
StatePublished - Aug 20 2008

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Amyloid
Water
Peptides
Trajectories
Molecular Dynamics Simulation
Molecular dynamics
Hydrophobic and Hydrophilic Interactions
Temperature
Computer simulation

All Science Journal Classification (ASJC) codes

  • Chemistry(all)

Cite this

Role of water in mediating the assembly of alzheimer amyloid-β Aβ16-22 protofilaments. / Krone, Mary Griffin; Hua, Lan; Soto, Patricia; Zhou, Ruhong; Berne, B. J.; Shea, Joan Emma.

In: Journal of the American Chemical Society, Vol. 130, No. 33, 20.08.2008, p. 11066-11072.

Research output: Contribution to journalArticle

Krone, Mary Griffin ; Hua, Lan ; Soto, Patricia ; Zhou, Ruhong ; Berne, B. J. ; Shea, Joan Emma. / Role of water in mediating the assembly of alzheimer amyloid-β Aβ16-22 protofilaments. In: Journal of the American Chemical Society. 2008 ; Vol. 130, No. 33. pp. 11066-11072.
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