dorsal/arxiv
View SchemaSolvent and mutation effects on the nucleation of amyloid $\beta$-protein folding
| Authors | Luis Cruz, Brigita Urbanc, Jose M. Borreguero, Noel D. Lazo, David B. Teplow, H. Eugene Stanley |
|---|---|
| Categories | |
| ArXiv ID | q-bio/0510048 |
| URL | https://arxiv.org/abs/q-bio/0510048 |
| DOI | 10.1073/pnas.0509276102 |
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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"abstract": "Experimental evidence suggests that the folding and aggregation of the\namyloid $\\beta$-protein (A$\\beta$) into oligomers is a key pathogenetic event\nin Alzheimer\u0027s disease (AD). Inhibiting the pathologic folding and\noligomerization of A$\\beta$ could be effective in the prevention and treatment\nof AD. Here, using all-atom molecular dynamics simulations in explicit solvent,\nwe probe the initial stages of folding of a decapeptide segment of A$\\beta$,\nA$\\beta_{21-30}$, shown experimentally to nucleate the folding process. In\naddition, we examine the folding of a homologous decapeptide containing an\namino acid substitution linked to hereditary cerebral hemorrhage with\namyloidosis--Dutch type, [Gln22]A$\\beta_{21-30}$. We find that: (i) when the\ndecapeptide is in water, hydrophobic interactions and transient salt bridges\nbetween Lys28 and either Glu22 or Asp23 are important in the formation of a\nloop in the Val24--Lys28 region of the wild type decapeptide; (ii) in the\npresence of salt ions, salt bridges play a more prominent role in the\nstabilization of the loop; (iii) in water with a reduced density, the\ndecapeptide forms a helix, indicating the sensitivity of folding to different\naqueous environments; (iv) the ``Dutch\u0027\u0027 peptide in water, in contrast to the\nwild type peptide, fails to form a long-lived Val24--Lys28 loop, suggesting\nthat loop stability is a critical factor in determining whether A$\\beta$ folds\ninto pathologic structures. Our results are relevant to understand the\nmechanism of A$\\beta$ peptide folding in different environments, such as intra-\nand extracellular milieus or cell membranes, and how amino acid substitutions\nlinked to familial forms of amyloidosis cause disease.",
"arxiv_id": "q-bio/0510048",
"authors": [
"Luis Cruz",
"Brigita Urbanc",
"Jose M. Borreguero",
"Noel D. Lazo",
"David B. Teplow",
"H. Eugene Stanley"
],
"categories": [
"q-bio.BM"
],
"doi": "10.1073/pnas.0509276102",
"title": "Solvent and mutation effects on the nucleation of amyloid $\\beta$-protein folding",
"url": "https://arxiv.org/abs/q-bio/0510048"
},
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