Cargando…
Heparin-Assisted Amyloidogenesis Uncovered through Molecular Dynamics Simulations
[Image: see text] Glycosaminoglycans (GAGs), in particular, heparan sulfate and heparin, are found colocalized with Aβ amyloid. They have been shown to enhance fibril formation, suggesting a possible pathological connection. We have investigated heparin’s assembly of the KLVFFA peptide fragment usin...
Autores principales: | , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical Society
2022
|
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9089684/ https://www.ncbi.nlm.nih.gov/pubmed/35572757 http://dx.doi.org/10.1021/acsomega.2c01034 |
_version_ | 1784704565844639744 |
---|---|
author | Khurshid, Beenish Rehman, Ashfaq Ur Luo, Ray Khan, Alamzeb Wadood, Abdul Anwar, Jamshed |
author_facet | Khurshid, Beenish Rehman, Ashfaq Ur Luo, Ray Khan, Alamzeb Wadood, Abdul Anwar, Jamshed |
author_sort | Khurshid, Beenish |
collection | PubMed |
description | [Image: see text] Glycosaminoglycans (GAGs), in particular, heparan sulfate and heparin, are found colocalized with Aβ amyloid. They have been shown to enhance fibril formation, suggesting a possible pathological connection. We have investigated heparin’s assembly of the KLVFFA peptide fragment using molecular dynamics simulation, to gain a molecular-level mechanistic understanding of how GAGs enhance fibril formation. The simulations reveal an exquisite process wherein heparin accelerates peptide assembly by first “gathering” the peptide molecules and then assembling them. Heparin does not act as a mere template but is tightly coupled to the peptides, yielding a composite protofilament structure. The strong intermolecular interactions suggest composite formation to be a general feature of heparin’s interaction with peptides. Heparin’s chain flexibility is found to be essential to its fibril promotion activity, and the need for optimal heparin chain length and concentration has been rationalized. These insights yield design rules (flexibility; chain-length) and protocol guidance (heparin:peptide molar ratio) for developing effective heparin mimetics and other functional GAGs. |
format | Online Article Text |
id | pubmed-9089684 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Chemical Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-90896842022-05-12 Heparin-Assisted Amyloidogenesis Uncovered through Molecular Dynamics Simulations Khurshid, Beenish Rehman, Ashfaq Ur Luo, Ray Khan, Alamzeb Wadood, Abdul Anwar, Jamshed ACS Omega [Image: see text] Glycosaminoglycans (GAGs), in particular, heparan sulfate and heparin, are found colocalized with Aβ amyloid. They have been shown to enhance fibril formation, suggesting a possible pathological connection. We have investigated heparin’s assembly of the KLVFFA peptide fragment using molecular dynamics simulation, to gain a molecular-level mechanistic understanding of how GAGs enhance fibril formation. The simulations reveal an exquisite process wherein heparin accelerates peptide assembly by first “gathering” the peptide molecules and then assembling them. Heparin does not act as a mere template but is tightly coupled to the peptides, yielding a composite protofilament structure. The strong intermolecular interactions suggest composite formation to be a general feature of heparin’s interaction with peptides. Heparin’s chain flexibility is found to be essential to its fibril promotion activity, and the need for optimal heparin chain length and concentration has been rationalized. These insights yield design rules (flexibility; chain-length) and protocol guidance (heparin:peptide molar ratio) for developing effective heparin mimetics and other functional GAGs. American Chemical Society 2022-04-21 /pmc/articles/PMC9089684/ /pubmed/35572757 http://dx.doi.org/10.1021/acsomega.2c01034 Text en © 2022 The Authors. Published by American Chemical Society https://creativecommons.org/licenses/by-nc-nd/4.0/Permits non-commercial access and re-use, provided that author attribution and integrity are maintained; but does not permit creation of adaptations or other derivative works (https://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Khurshid, Beenish Rehman, Ashfaq Ur Luo, Ray Khan, Alamzeb Wadood, Abdul Anwar, Jamshed Heparin-Assisted Amyloidogenesis Uncovered through Molecular Dynamics Simulations |
title | Heparin-Assisted Amyloidogenesis Uncovered through
Molecular Dynamics Simulations |
title_full | Heparin-Assisted Amyloidogenesis Uncovered through
Molecular Dynamics Simulations |
title_fullStr | Heparin-Assisted Amyloidogenesis Uncovered through
Molecular Dynamics Simulations |
title_full_unstemmed | Heparin-Assisted Amyloidogenesis Uncovered through
Molecular Dynamics Simulations |
title_short | Heparin-Assisted Amyloidogenesis Uncovered through
Molecular Dynamics Simulations |
title_sort | heparin-assisted amyloidogenesis uncovered through
molecular dynamics simulations |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9089684/ https://www.ncbi.nlm.nih.gov/pubmed/35572757 http://dx.doi.org/10.1021/acsomega.2c01034 |
work_keys_str_mv | AT khurshidbeenish heparinassistedamyloidogenesisuncoveredthroughmoleculardynamicssimulations AT rehmanashfaqur heparinassistedamyloidogenesisuncoveredthroughmoleculardynamicssimulations AT luoray heparinassistedamyloidogenesisuncoveredthroughmoleculardynamicssimulations AT khanalamzeb heparinassistedamyloidogenesisuncoveredthroughmoleculardynamicssimulations AT wadoodabdul heparinassistedamyloidogenesisuncoveredthroughmoleculardynamicssimulations AT anwarjamshed heparinassistedamyloidogenesisuncoveredthroughmoleculardynamicssimulations |