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Dimer Formation Enhances Structural Differences between Amyloid β-Protein (1–40) and (1–42): An Explicit-Solvent Molecular Dynamics Study
Amyloid [Image: see text]-protein (A[Image: see text]) is central to the pathology of Alzheimer's disease. A 5% difference in the primary structure of the two predominant alloforms, A[Image: see text] and A[Image: see text], results in distinct assembly pathways and toxicity properties. Discret...
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2012
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3324527/ https://www.ncbi.nlm.nih.gov/pubmed/22509291 http://dx.doi.org/10.1371/journal.pone.0034345 |
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author | Barz, Bogdan Urbanc, Brigita |
author_facet | Barz, Bogdan Urbanc, Brigita |
author_sort | Barz, Bogdan |
collection | PubMed |
description | Amyloid [Image: see text]-protein (A[Image: see text]) is central to the pathology of Alzheimer's disease. A 5% difference in the primary structure of the two predominant alloforms, A[Image: see text] and A[Image: see text], results in distinct assembly pathways and toxicity properties. Discrete molecular dynamics (DMD) studies of A[Image: see text] and A[Image: see text] assembly resulted in alloform-specific oligomer size distributions consistent with experimental findings. Here, a large ensemble of DMD–derived A[Image: see text] and A[Image: see text] monomers and dimers was subjected to fully atomistic molecular dynamics (MD) simulations using the OPLS-AA force field combined with two water models, SPCE and TIP3P. The resulting all-atom conformations were slightly larger, less compact, had similar turn and lower [Image: see text]-strand propensities than those predicted by DMD. Fully atomistic A[Image: see text] and A[Image: see text] monomers populated qualitatively similar free energy landscapes. In contrast, the free energy landscape of A[Image: see text] dimers indicated a larger conformational variability in comparison to that of A[Image: see text] dimers. A[Image: see text] dimers were characterized by an increased flexibility in the N-terminal region D1-R5 and a larger solvent exposure of charged amino acids relative to A[Image: see text] dimers. Of the three positively charged amino acids, R5 was the most and K16 the least involved in salt bridge formation. This result was independent of the water model, alloform, and assembly state. Overall, salt bridge propensities increased upon dimer formation. An exception was the salt bridge propensity of K28, which decreased upon formation of A[Image: see text] dimers and was significantly lower than in A[Image: see text] dimers. The potential relevance of the three positively charged amino acids in mediating the A[Image: see text] oligomer toxicity is discussed in the light of available experimental data. |
format | Online Article Text |
id | pubmed-3324527 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-33245272012-04-16 Dimer Formation Enhances Structural Differences between Amyloid β-Protein (1–40) and (1–42): An Explicit-Solvent Molecular Dynamics Study Barz, Bogdan Urbanc, Brigita PLoS One Research Article Amyloid [Image: see text]-protein (A[Image: see text]) is central to the pathology of Alzheimer's disease. A 5% difference in the primary structure of the two predominant alloforms, A[Image: see text] and A[Image: see text], results in distinct assembly pathways and toxicity properties. Discrete molecular dynamics (DMD) studies of A[Image: see text] and A[Image: see text] assembly resulted in alloform-specific oligomer size distributions consistent with experimental findings. Here, a large ensemble of DMD–derived A[Image: see text] and A[Image: see text] monomers and dimers was subjected to fully atomistic molecular dynamics (MD) simulations using the OPLS-AA force field combined with two water models, SPCE and TIP3P. The resulting all-atom conformations were slightly larger, less compact, had similar turn and lower [Image: see text]-strand propensities than those predicted by DMD. Fully atomistic A[Image: see text] and A[Image: see text] monomers populated qualitatively similar free energy landscapes. In contrast, the free energy landscape of A[Image: see text] dimers indicated a larger conformational variability in comparison to that of A[Image: see text] dimers. A[Image: see text] dimers were characterized by an increased flexibility in the N-terminal region D1-R5 and a larger solvent exposure of charged amino acids relative to A[Image: see text] dimers. Of the three positively charged amino acids, R5 was the most and K16 the least involved in salt bridge formation. This result was independent of the water model, alloform, and assembly state. Overall, salt bridge propensities increased upon dimer formation. An exception was the salt bridge propensity of K28, which decreased upon formation of A[Image: see text] dimers and was significantly lower than in A[Image: see text] dimers. The potential relevance of the three positively charged amino acids in mediating the A[Image: see text] oligomer toxicity is discussed in the light of available experimental data. Public Library of Science 2012-04-11 /pmc/articles/PMC3324527/ /pubmed/22509291 http://dx.doi.org/10.1371/journal.pone.0034345 Text en Barz, Urbanc. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Barz, Bogdan Urbanc, Brigita Dimer Formation Enhances Structural Differences between Amyloid β-Protein (1–40) and (1–42): An Explicit-Solvent Molecular Dynamics Study |
title | Dimer Formation Enhances Structural Differences between Amyloid β-Protein (1–40) and (1–42): An Explicit-Solvent Molecular Dynamics Study |
title_full | Dimer Formation Enhances Structural Differences between Amyloid β-Protein (1–40) and (1–42): An Explicit-Solvent Molecular Dynamics Study |
title_fullStr | Dimer Formation Enhances Structural Differences between Amyloid β-Protein (1–40) and (1–42): An Explicit-Solvent Molecular Dynamics Study |
title_full_unstemmed | Dimer Formation Enhances Structural Differences between Amyloid β-Protein (1–40) and (1–42): An Explicit-Solvent Molecular Dynamics Study |
title_short | Dimer Formation Enhances Structural Differences between Amyloid β-Protein (1–40) and (1–42): An Explicit-Solvent Molecular Dynamics Study |
title_sort | dimer formation enhances structural differences between amyloid β-protein (1–40) and (1–42): an explicit-solvent molecular dynamics study |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3324527/ https://www.ncbi.nlm.nih.gov/pubmed/22509291 http://dx.doi.org/10.1371/journal.pone.0034345 |
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