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Solvent and mutation effects on the nucleation of amyloid $\beta$-protein folding
Biomolecules · Submitted 26 Oct 2005
abstract compiled · 2026-09-23 · no language-model review
The authors' main claim We find that: (i) when the decapeptide is in water, hydrophobic interactions and transient salt bridges between Lys28 and either Glu22 or Asp23 are important in the formation of a loop in the Val24--Lys28 region of the wild type decapeptide; (ii) in the presence of salt ions, salt bridges play a more prominent role in the stabilization of the loop; (iii) in water with a reduced density, the decapeptide forms a helix, indicating the sensitivity of folding to different aqueous environments; (iv) the ``Dutch'' peptide in water, in contrast to the wild type peptide, fails to form a long-lived Val24--Lys28 loop, suggesting that loop stability is a critical factor in determining whether A$\beta$ folds into pathologic structures.
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The abstract, sentence by sentence
Experimental evidence suggests that the folding and aggregation of the amyloid $\beta$-protein (A$\beta$) into oligomers is a key pathogenetic event in Alzheimer's disease (AD). Inhibiting the pathologic folding and oligomerization of A$\beta$ could be effective in the prevention and treatment of AD. Here, using all-atom molecular dynamics simulations in explicit solvent, we probe the initial stages of folding of a decapeptide segment of A$\beta$, A$\beta_{21-30}$, shown experimentally to nucleate the folding process. In addition, we examine the folding of a homologous decapeptide containing an amino acid substitution linked to hereditary cerebral hemorrhage with amyloidosis--Dutch type, [Gln22]A$\beta_{21-30}$. We find that: (i) when the decapeptide is in water, hydrophobic interactions and transient salt bridges between Lys28 and either Glu22 or Asp23 are important in the formation of a loop in the Val24--Lys28 region of the wild type decapeptide; (ii) in the presence of salt ions, salt bridges play a more prominent role in the stabilization of the loop; (iii) in water with a reduced density, the decapeptide forms a helix, indicating the sensitivity of folding to different aqueous environments; (iv) the ``Dutch'' peptide in water, in contrast to the wild type peptide, fails to form a long-lived Val24--Lys28 loop, suggesting that loop stability is a critical factor in determining whether A$\beta$ folds into pathologic structures. Our results are relevant to understand the mechanism of A$\beta$ peptide folding in different environments, such as intra- and extracellular milieus or cell membranes, and how amino acid substitutions linked to familial forms of amyloidosis cause disease.
background contribution method result interpretation main claim
| # | sentence | role | the authors' own work | states the main conclusion | strength |
|---|---|---|---|---|---|
| s0 | Experimental evidence suggests that the folding and aggregation of the amyloid $\beta$-protein (A$\beta$) into oligomers is a key pathogenetic event in Alzheimer's disease (AD). | background 1.00 | 0.06 | 0.03 | hedged possibility 0.99 |
| s1 | Inhibiting the pathologic folding and oligomerization of A$\beta$ could be effective in the prevention and treatment of AD. | background 0.98 | 0.04 | 0.04 | hedged possibility 1.00 |
| s2 | Here, using all-atom molecular dynamics simulations in explicit solvent, we probe the initial stages of folding of a decapeptide segment of A$\beta$, A$\beta_{21-30}$, shown experimentally to nucleate the folding process. | contribution 0.60 | 0.94 | 0.03 | asserted 0.94 |
| s3 | In addition, we examine the folding of a homologous decapeptide containing an amino acid substitution linked to hereditary cerebral hemorrhage with amyloidosis--Dutch type, [Gln22]A$\beta_{21-30}$. | contribution 0.76 | 0.87 | 0.03 | asserted 0.84 |
| s4 | We find that: (i) when the decapeptide is in water, hydrophobic interactions and transient salt bridges between Lys28 and either Glu22 or Asp23 are important in the formation of a loop in the Val24--Lys28 region of the wild type decapeptide; (ii) in the presence of salt ions, salt bridges play a more prominent role in the stabilization of the loop; (iii) in water with a reduced density, the decapeptide forms a helix, indicating the sensitivity of folding to different aqueous environments; (iv) the ``Dutch'' peptide in water, in contrast to the wild type peptide, fails to form a long-lived Val24--Lys28 loop, suggesting that loop stability is a critical factor in determining whether A$\beta$ folds into pathologic structures. | result 1.00 | 0.97 | 0.81 | asserted 0.89 |
| s5 | Our results are relevant to understand the mechanism of A$\beta$ peptide folding in different environments, such as intra- and extracellular milieus or cell membranes, and how amino acid substitutions linked to familial forms of amyloidosis cause disease. | interpretation 1.00 | 0.37 | 0.17 | asserted 0.61 |
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The paper
Original abstract
Experimental evidence suggests that the folding and aggregation of the amyloid $\beta$-protein (A$\beta$) into oligomers is a key pathogenetic event in Alzheimer's disease (AD). Inhibiting the pathologic folding and oligomerization of A$\beta$ could be effective in the prevention and treatment of AD. Here, using all-atom molecular dynamics simulations in explicit solvent, we probe the initial stages of folding of a decapeptide segment of A$\beta$, A$\beta_{21-30}$, shown experimentally to nucleate the folding process. In addition, we examine the folding of a homologous decapeptide containing an amino acid substitution linked to hereditary cerebral hemorrhage with amyloidosis--Dutch type, [Gln22]A$\beta_{21-30}$. We find that: (i) when the decapeptide is in water, hydrophobic interactions and transient salt bridges between Lys28 and either Glu22 or Asp23 are important in the formation of a loop in the Val24--Lys28 region of the wild type decapeptide; (ii) in the presence of salt ions, salt bridges play a more prominent role in the stabilization of the loop; (iii) in water with a reduced density, the decapeptide forms a helix, indicating the sensitivity of folding to different aqueous environments; (iv) the ``Dutch'' peptide in water, in contrast to the wild type peptide, fails to form a long-lived Val24--Lys28 loop, suggesting that loop stability is a critical factor in determining whether A$\beta$ folds into pathologic structures. Our results are relevant to understand the mechanism of A$\beta$ peptide folding in different environments, such as intra- and extracellular milieus or cell membranes, and how amino acid substitutions linked to familial forms of amyloidosis cause disease.
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