Elucidation of Amyloid β-Protein Oligomerization Mechanisms: Discrete Molecular Dynamics Study
Oligomers of amyloid beta-protein (Abeta) play a central role in the pathology of Alzheimer's disease. Of the two predominant Abeta alloforms, Abeta(1-40) and Abeta(1-42), Abeta(1-42) is more strongly implicated in the disease. We elucidated the structural characteristics of oligomers of Abeta(...
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ftcdlib:oai:escholarship.org:ark:/13030/qt4vw301bx 2023-09-05T13:17:01+02:00 Elucidation of Amyloid β-Protein Oligomerization Mechanisms: Discrete Molecular Dynamics Study Urbanc, B Betnel, M Cruz, L Bitan, G Teplow, DB 4266 - 4280 2010-03-31 application/pdf https://escholarship.org/uc/item/4vw301bx unknown eScholarship, University of California qt4vw301bx https://escholarship.org/uc/item/4vw301bx public Journal of the American Chemical Society, vol 132, iss 12 Dementia Alzheimer's Disease Acquired Cognitive Impairment Brain Disorders Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) Neurosciences Aging Neurodegenerative 2.1 Biological and endogenous factors Aetiology Amino Acid Sequence Amyloid beta-Peptides Models Molecular Molecular Dynamics Simulation Molecular Sequence Data Static Electricity Water Chemical Sciences General Chemistry article 2010 ftcdlib 2023-08-21T18:06:45Z Oligomers of amyloid beta-protein (Abeta) play a central role in the pathology of Alzheimer's disease. Of the two predominant Abeta alloforms, Abeta(1-40) and Abeta(1-42), Abeta(1-42) is more strongly implicated in the disease. We elucidated the structural characteristics of oligomers of Abeta(1-40) and Abeta(1-42) and their Arctic mutants, [E22G]Abeta(1-40) and [E22G]Abeta(1-42). We simulated oligomer formation using discrete molecular dynamics (DMD) with a four-bead protein model, backbone hydrogen bonding, and residue-specific interactions due to effective hydropathy and charge. For all four peptides under study, we derived the characteristic oligomer size distributions that were in agreement with prior experimental findings. Unlike Abeta(1-40), Abeta(1-42) had a high propensity to form paranuclei (pentameric or hexameric) structures that could self-associate into higher-order oligomers. Neither of the Arctic mutants formed higher-order oligomers, but [E22G]Abeta(1-40) formed paranuclei with a similar propensity to that of Abeta(1-42). Whereas the best agreement with the experimental data was obtained when the charged residues were modeled as solely hydrophilic, further assembly from spherical oligomers into elongated protofibrils was induced by nonzero electrostatic interactions among the charged residues. Structural analysis revealed that the C-terminal region played a dominant role in Abeta(1-42) oligomer formation whereas Abeta(1-40) oligomerization was primarily driven by intermolecular interactions among the central hydrophobic regions. The N-terminal region A2-F4 played a prominent role in Abeta(1-40) oligomerization but did not contribute to the oligomerization of Abeta(1-42) or the Arctic mutants. The oligomer structure of both Arctic peptides resembled Abeta(1-42) more than Abeta(1-40), consistent with their potentially more toxic nature. Article in Journal/Newspaper Arctic University of California: eScholarship Arctic |
institution |
Open Polar |
collection |
University of California: eScholarship |
op_collection_id |
ftcdlib |
language |
unknown |
topic |
Dementia Alzheimer's Disease Acquired Cognitive Impairment Brain Disorders Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) Neurosciences Aging Neurodegenerative 2.1 Biological and endogenous factors Aetiology Amino Acid Sequence Amyloid beta-Peptides Models Molecular Molecular Dynamics Simulation Molecular Sequence Data Static Electricity Water Chemical Sciences General Chemistry |
spellingShingle |
Dementia Alzheimer's Disease Acquired Cognitive Impairment Brain Disorders Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) Neurosciences Aging Neurodegenerative 2.1 Biological and endogenous factors Aetiology Amino Acid Sequence Amyloid beta-Peptides Models Molecular Molecular Dynamics Simulation Molecular Sequence Data Static Electricity Water Chemical Sciences General Chemistry Urbanc, B Betnel, M Cruz, L Bitan, G Teplow, DB Elucidation of Amyloid β-Protein Oligomerization Mechanisms: Discrete Molecular Dynamics Study |
topic_facet |
Dementia Alzheimer's Disease Acquired Cognitive Impairment Brain Disorders Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) Neurosciences Aging Neurodegenerative 2.1 Biological and endogenous factors Aetiology Amino Acid Sequence Amyloid beta-Peptides Models Molecular Molecular Dynamics Simulation Molecular Sequence Data Static Electricity Water Chemical Sciences General Chemistry |
description |
Oligomers of amyloid beta-protein (Abeta) play a central role in the pathology of Alzheimer's disease. Of the two predominant Abeta alloforms, Abeta(1-40) and Abeta(1-42), Abeta(1-42) is more strongly implicated in the disease. We elucidated the structural characteristics of oligomers of Abeta(1-40) and Abeta(1-42) and their Arctic mutants, [E22G]Abeta(1-40) and [E22G]Abeta(1-42). We simulated oligomer formation using discrete molecular dynamics (DMD) with a four-bead protein model, backbone hydrogen bonding, and residue-specific interactions due to effective hydropathy and charge. For all four peptides under study, we derived the characteristic oligomer size distributions that were in agreement with prior experimental findings. Unlike Abeta(1-40), Abeta(1-42) had a high propensity to form paranuclei (pentameric or hexameric) structures that could self-associate into higher-order oligomers. Neither of the Arctic mutants formed higher-order oligomers, but [E22G]Abeta(1-40) formed paranuclei with a similar propensity to that of Abeta(1-42). Whereas the best agreement with the experimental data was obtained when the charged residues were modeled as solely hydrophilic, further assembly from spherical oligomers into elongated protofibrils was induced by nonzero electrostatic interactions among the charged residues. Structural analysis revealed that the C-terminal region played a dominant role in Abeta(1-42) oligomer formation whereas Abeta(1-40) oligomerization was primarily driven by intermolecular interactions among the central hydrophobic regions. The N-terminal region A2-F4 played a prominent role in Abeta(1-40) oligomerization but did not contribute to the oligomerization of Abeta(1-42) or the Arctic mutants. The oligomer structure of both Arctic peptides resembled Abeta(1-42) more than Abeta(1-40), consistent with their potentially more toxic nature. |
format |
Article in Journal/Newspaper |
author |
Urbanc, B Betnel, M Cruz, L Bitan, G Teplow, DB |
author_facet |
Urbanc, B Betnel, M Cruz, L Bitan, G Teplow, DB |
author_sort |
Urbanc, B |
title |
Elucidation of Amyloid β-Protein Oligomerization Mechanisms: Discrete Molecular Dynamics Study |
title_short |
Elucidation of Amyloid β-Protein Oligomerization Mechanisms: Discrete Molecular Dynamics Study |
title_full |
Elucidation of Amyloid β-Protein Oligomerization Mechanisms: Discrete Molecular Dynamics Study |
title_fullStr |
Elucidation of Amyloid β-Protein Oligomerization Mechanisms: Discrete Molecular Dynamics Study |
title_full_unstemmed |
Elucidation of Amyloid β-Protein Oligomerization Mechanisms: Discrete Molecular Dynamics Study |
title_sort |
elucidation of amyloid β-protein oligomerization mechanisms: discrete molecular dynamics study |
publisher |
eScholarship, University of California |
publishDate |
2010 |
url |
https://escholarship.org/uc/item/4vw301bx |
op_coverage |
4266 - 4280 |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
Journal of the American Chemical Society, vol 132, iss 12 |
op_relation |
qt4vw301bx https://escholarship.org/uc/item/4vw301bx |
op_rights |
public |
_version_ |
1776198375577747456 |