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Computational Design of New Peptide Inhibitors for Amyloid Beta (Aβ) Aggregation in Alzheimer's Disease: Application of a Novel Methodology

Alzheimer's disease is the most common form of dementia. It is a neurodegenerative and incurable disease that is associated with the tight packing of amyloid fibrils. This packing is facilitated by the compatibility of the ridges and grooves on the amyloid surface. The GxMxG motif is the major...

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Autores principales: Eskici, Gözde, Gur, Mert
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3675214/
https://www.ncbi.nlm.nih.gov/pubmed/23762479
http://dx.doi.org/10.1371/journal.pone.0066178
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author Eskici, Gözde
Gur, Mert
author_facet Eskici, Gözde
Gur, Mert
author_sort Eskici, Gözde
collection PubMed
description Alzheimer's disease is the most common form of dementia. It is a neurodegenerative and incurable disease that is associated with the tight packing of amyloid fibrils. This packing is facilitated by the compatibility of the ridges and grooves on the amyloid surface. The GxMxG motif is the major factor creating the compatibility between two amyloid surfaces, making it an important target for the design of amyloid aggregation inhibitors. In this study, a peptide, experimentally proven to bind Aβ40 fibrils at the GxMxG motif, was mutated by a novel methodology that systematically replaces amino acids with residues that share similar chemical characteristics and subsequently assesses the energetic favorability of these mutations by docking. Successive mutations are combined and reassessed via docking to a desired level of refinement. This methodology is both fast and efficient in providing potential inhibitors. Its efficiency lies in the fact that it does not perform all possible combinations of mutations, therefore decreasing the computational time drastically. The binding free energies of the experimentally studied reference peptide and its three top scoring derivatives were evaluated as a final assessment/valuation. The potential of mean forces (PMFs) were calculated by applying the Jarzynski‚s equality to results of steered molecular dynamics simulations. For all of the top scoring derivatives, the PMFs showed higher binding free energies than the reference peptide substantiating the usage of the introduced methodology to drug design.
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spelling pubmed-36752142013-06-12 Computational Design of New Peptide Inhibitors for Amyloid Beta (Aβ) Aggregation in Alzheimer's Disease: Application of a Novel Methodology Eskici, Gözde Gur, Mert PLoS One Research Article Alzheimer's disease is the most common form of dementia. It is a neurodegenerative and incurable disease that is associated with the tight packing of amyloid fibrils. This packing is facilitated by the compatibility of the ridges and grooves on the amyloid surface. The GxMxG motif is the major factor creating the compatibility between two amyloid surfaces, making it an important target for the design of amyloid aggregation inhibitors. In this study, a peptide, experimentally proven to bind Aβ40 fibrils at the GxMxG motif, was mutated by a novel methodology that systematically replaces amino acids with residues that share similar chemical characteristics and subsequently assesses the energetic favorability of these mutations by docking. Successive mutations are combined and reassessed via docking to a desired level of refinement. This methodology is both fast and efficient in providing potential inhibitors. Its efficiency lies in the fact that it does not perform all possible combinations of mutations, therefore decreasing the computational time drastically. The binding free energies of the experimentally studied reference peptide and its three top scoring derivatives were evaluated as a final assessment/valuation. The potential of mean forces (PMFs) were calculated by applying the Jarzynski‚s equality to results of steered molecular dynamics simulations. For all of the top scoring derivatives, the PMFs showed higher binding free energies than the reference peptide substantiating the usage of the introduced methodology to drug design. Public Library of Science 2013-06-06 /pmc/articles/PMC3675214/ /pubmed/23762479 http://dx.doi.org/10.1371/journal.pone.0066178 Text en © 2013 Eskici and Gur 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
Eskici, Gözde
Gur, Mert
Computational Design of New Peptide Inhibitors for Amyloid Beta (Aβ) Aggregation in Alzheimer's Disease: Application of a Novel Methodology
title Computational Design of New Peptide Inhibitors for Amyloid Beta (Aβ) Aggregation in Alzheimer's Disease: Application of a Novel Methodology
title_full Computational Design of New Peptide Inhibitors for Amyloid Beta (Aβ) Aggregation in Alzheimer's Disease: Application of a Novel Methodology
title_fullStr Computational Design of New Peptide Inhibitors for Amyloid Beta (Aβ) Aggregation in Alzheimer's Disease: Application of a Novel Methodology
title_full_unstemmed Computational Design of New Peptide Inhibitors for Amyloid Beta (Aβ) Aggregation in Alzheimer's Disease: Application of a Novel Methodology
title_short Computational Design of New Peptide Inhibitors for Amyloid Beta (Aβ) Aggregation in Alzheimer's Disease: Application of a Novel Methodology
title_sort computational design of new peptide inhibitors for amyloid beta (aβ) aggregation in alzheimer's disease: application of a novel methodology
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3675214/
https://www.ncbi.nlm.nih.gov/pubmed/23762479
http://dx.doi.org/10.1371/journal.pone.0066178
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