Solid-state NMR study shows that the 22-residue K3 peptide (Ser
20
-Lys
41
) from
β
2
-microglobulin (
β
2
m) adopts a
β
-strand-loop-
β
-strand conformation in its fibril state. Residue Pro
32
has a
...trans
conformation in the fibril state of the peptide, while it adopts a
cis
conformation in the native state of full-length
β
2
m. To get insights into the structural properties of the K3 peptide, and determine whether the strand-loop-strand conformation is encoded at the monomeric level, we run all-atom explicit solvent replica exchange molecular dynamics on both the
cis
and
trans
variants. Our simulations show that the conformational space of the
trans
- and
cis
-K3 peptides is very different, with 1% of the sampled conformations in common at room temperature. In addition, both variants display only 0.3–0.5% of the conformations with
β
-strand-loop-
β
-strand character. This finding, compared to results on the Alzheimer's A
β
peptide, suggests that the biases toward aggregation leading to the
β
-strand-loop-
β
-strand conformation in fibrils are peptide-dependent.
Many human neurodegenerative diseases are associated with amyloid fibril formation. The human 99-residue beta(2)-microglobulin (beta2m) is one of the most intensively studied amyloid-forming ...proteins. Recent studies show that the C-terminal fragments 72-99, 83-89, and 91-96 form by themselves amyloid fibrils in vitro and play a significant role in fibrillization of the full-length beta2m protein under acidic pH conditions. In this work, we have studied the equilibrium structures of the 17-residue fragment 83-99 in solution, and investigated its dimerization process by multiple molecular dynamics simulations. We find that an intertwined dimer, with the positions of the beta-strands consistent with the results for the monomer, is a possible structure for two beta2m(83-89) peptides. Based on our molecular-dynamics-generated dimeric structure, a protofibril model is proposed for the full-length beta2m protein.
Many human neurodegenerative diseases are associated with amyloid fibril formation. The human 99-residue β^sub 2^-microglobulin (β2m) is one of the most intensively studied amyloid-forming proteins. ...Recent studies show that the C-terminal fragments 72-99, 83-89, and 91-56 form by themselves amyloid fibrils in vitro and play a significant role in fibrillization of the full-length β2m protein under acidic pH conditions. In this work, we have studied the equilibrium structures of the 17-residue fragment 83-99 in solution, and investigated its dimerization process by multiple molecular dynamics simulations. We find that an intertwined dimer, with the positions of the β-strands consistent with the results for the monomer, is a possible structure for two β2m(83-89) peptides. Based on our molecular-dynamics-generated dimeric structure, a protofibril model is proposed for the full-length β2m protein. PUBLICATION ABSTRACT
Many human neurodegenerative diseases are associated with amyloid fibril formation. The human 99-residue beta sub(2-microglobulin (beta2m) is one of the most intensively studied amyloid-forming ...proteins. Recent studies show that the C-terminal fragments 72-99, 83-89, and 91-96 form by themselves amyloid fibrils in vitro and play a significant role in fibrillization of the full-length beta2m protein under acidic pH conditions. In this work, we have studied the equilibrium structures of the 17-residue fragment 83-99 in solution, and investigated its dimerization process by multiple molecular dynamics simulations. We find that an intertwined dimer, with the positions of the beta-strands consistent with the results for the monomer, is a possible structure for two beta2m(83-89) peptides. Based on our molecular-dynamics-generated dimeric structure, a protofibril model is proposed for the full-length beta2m protein.)
Solid-state NMR study shows that the 22-residue K3 peptide (Ser^sup 20^-Lys^sup 41^) from β^sub 2^-microglobulin (β^sub 2^m) adopts a β-strand-loop-β-strand conformation in its fibril state. Residue ...Pro^sup 32^ has a trans conformation in the fibril state of the peptide, while it adopts a cis conformation in the native state of full-length β^sub 2^m. To get insights into the structural properties of the K3 peptide, and determine whether the strand-loop-strand conformation is encoded at the monomeric level, we run all-atom explicit solvent replica exchange molecular dynamics on both the cis and trans variants. Our simulations show that the conformational space of the trans- and cis-K3 peptides is very different, with 1% of the sampled conformations in common at room temperature. In addition, both variants display only 0.3-0.5% of the conformations with β-strand-loop-β-strand character. This finding, compared to results on the AlZheimefs Aβ peptide, suggests that the biases toward aggregation leading to the β-strand-loop-β-strand conformation in fibrils are peptide-dependent. PUBLICATION ABSTRACT
Solid-state NMR study shows that the 22-residue K3 peptide (Sersuper20-Lyssuper41) from beta sub(2-microglobulin (beta) sub(2)m) adopts a beta-strand-loop-beta-strand conformation in its fibril ...state. Residue Prosuper32 has a trans conformation in the fibril state of the peptide, while it adopts a cis conformation in the native state of full-length beta sub(2m. To get insights into the structural properties of the K3 peptide, and determine whether the strand-loop-strand conformation is encoded at the monomeric level, we run all-atom explicit solvent replica exchange molecular dynamics on both the cis and trans variants. Our simulations show that the conformational space of the trans- and cis-K3 peptides is very different, with 1% of the sampled conformations in common at room temperature. In addition, both variants display only 0.3-0.5% of the conformations with beta-strand-loop-beta-strand character. This finding, compared to results on the Alzheimer's Abeta peptide, suggests that the biases toward aggregation leading to the beta-strand-loop-beta-strand conformation in fibrils are peptide-dependent.)
Solid-state NMR study shows that the 22-residue K3 peptide (Ser
20-Lys
41) from
β
2-microglobulin (
β
2m) adopts a
β-strand-loop-
β-strand conformation in its fibril state. Residue Pro
32 has a
trans ...conformation in the fibril state of the peptide, while it adopts a
cis conformation in the native state of full-length
β
2m. To get insights into the structural properties of the K3 peptide, and determine whether the strand-loop-strand conformation is encoded at the monomeric level, we run all-atom explicit solvent replica exchange molecular dynamics on both the
cis and
trans variants. Our simulations show that the conformational space of the
trans- and
cis-K3 peptides is very different, with 1% of the sampled conformations in common at room temperature. In addition, both variants display only 0.3–0.5% of the conformations with
β-strand-loop-
β-strand character. This finding, compared to results on the Alzheimer's A
β peptide, suggests that the biases toward aggregation leading to the
β-strand-loop-
β-strand conformation in fibrils are peptide-dependent.
Solid-state NMR study shows that the 22-residue K3 peptide (Ser(20)-Lys(41)) from beta(2)-microglobulin (beta(2)m) adopts a beta-strand-loop-beta-strand conformation in its fibril state. Residue ...Pro(32) has a trans conformation in the fibril state of the peptide, while it adopts a cis conformation in the native state of full-length beta(2)m. To get insights into the structural properties of the K3 peptide, and determine whether the strand-loop-strand conformation is encoded at the monomeric level, we run all-atom explicit solvent replica exchange molecular dynamics on both the cis and trans variants. Our simulations show that the conformational space of the trans- and cis-K3 peptides is very different, with 1% of the sampled conformations in common at room temperature. In addition, both variants display only 0.3-0.5% of the conformations with beta-strand-loop-beta-strand character. This finding, compared to results on the Alzheimer's Abeta peptide, suggests that the biases toward aggregation leading to the beta-strand-loop-beta-strand conformation in fibrils are peptide-dependent.
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