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 language | English |
|---|---|
| Pages (from-to) | 11066-11072 |
| Number of pages | 7 |
| Journal | Journal of the American Chemical Society |
| Volume | 130 |
| Issue number | 33 |
| DOIs | |
| State | Published - Aug 20 2008 |
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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 journal › Article
}
TY - JOUR
T1 - Role of water in mediating the assembly of alzheimer amyloid-β Aβ16-22 protofilaments
AU - Krone, Mary Griffin
AU - Hua, Lan
AU - Soto, Patricia
AU - Zhou, Ruhong
AU - Berne, B. J.
AU - Shea, Joan Emma
PY - 2008/8/20
Y1 - 2008/8/20
N2 - 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.
AB - 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.
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U2 - 10.1021/ja8017303
DO - 10.1021/ja8017303
M3 - Article
VL - 130
SP - 11066
EP - 11072
JO - Journal of the American Chemical Society
JF - Journal of the American Chemical Society
SN - 0002-7863
IS - 33
ER -