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Docking and Molecular Dynamics-Based Identification of Interaction between Various Beta-Amyloid Isoforms and RAGE Receptor
Beta-amyloid peptide (Aβ) is a ligand associated with RAGE (Advanced glycosylation end product-specific receptor). Aβ is translocated in complexes with RAGE from the blood to brain across the blood–brain barrier (BBB) by transcytosis. Aβ and its isoforms are important factors in the Alzheimer’s dise...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9570301/ https://www.ncbi.nlm.nih.gov/pubmed/36233130 http://dx.doi.org/10.3390/ijms231911816 |
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author | Tolstova, Anna P. Adzhubei, Alexei A. Mitkevich, Vladimir A. Petrushanko, Irina Yu. Makarov, Alexander A. |
author_facet | Tolstova, Anna P. Adzhubei, Alexei A. Mitkevich, Vladimir A. Petrushanko, Irina Yu. Makarov, Alexander A. |
author_sort | Tolstova, Anna P. |
collection | PubMed |
description | Beta-amyloid peptide (Aβ) is a ligand associated with RAGE (Advanced glycosylation end product-specific receptor). Aβ is translocated in complexes with RAGE from the blood to brain across the blood–brain barrier (BBB) by transcytosis. Aβ and its isoforms are important factors in the Alzheimer’s disease (AD) pathogenesis. However, interaction with RAGE was previously studied for Aβ but not for its isoforms. The present study has been directed at identifying the key interaction interfaces between RAGE and Aβ isoforms (Aβ(40), Aβ(42), phosphorylated and isomerized isoforms pS8-Aβ(42), isoD7-Aβ(42)). Two interfaces have been identified by docking: they are represented by an extended area at the junction of RAGE domains V and C1 and a smaller area linking C1 and C2 domains. Molecular dynamics (MD) simulations have shown that all Aβ isoforms form stable and tightly bound complexes. This indicates that all Aβ isoforms potentially can be transported through the cell as part of a complex with RAGE. Modeling of RAGE interaction interfaces with Aβ indicates which chemical compounds can potentially be capable of blocking this interaction, and impair the associated pathogenic cascades. The ability of three RAGE inhibitors (RAP, FPS-ZM1 and RP-1) to disrupt the RAGE:Aβ interaction has been probed by docking and subsequently the complexes’ stability verified by MD. The RP-1 and Aβ interaction areas coincide and therefore this inhibitor is very promising for the RAGE:Aβ interaction inhibition. |
format | Online Article Text |
id | pubmed-9570301 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-95703012022-10-17 Docking and Molecular Dynamics-Based Identification of Interaction between Various Beta-Amyloid Isoforms and RAGE Receptor Tolstova, Anna P. Adzhubei, Alexei A. Mitkevich, Vladimir A. Petrushanko, Irina Yu. Makarov, Alexander A. Int J Mol Sci Article Beta-amyloid peptide (Aβ) is a ligand associated with RAGE (Advanced glycosylation end product-specific receptor). Aβ is translocated in complexes with RAGE from the blood to brain across the blood–brain barrier (BBB) by transcytosis. Aβ and its isoforms are important factors in the Alzheimer’s disease (AD) pathogenesis. However, interaction with RAGE was previously studied for Aβ but not for its isoforms. The present study has been directed at identifying the key interaction interfaces between RAGE and Aβ isoforms (Aβ(40), Aβ(42), phosphorylated and isomerized isoforms pS8-Aβ(42), isoD7-Aβ(42)). Two interfaces have been identified by docking: they are represented by an extended area at the junction of RAGE domains V and C1 and a smaller area linking C1 and C2 domains. Molecular dynamics (MD) simulations have shown that all Aβ isoforms form stable and tightly bound complexes. This indicates that all Aβ isoforms potentially can be transported through the cell as part of a complex with RAGE. Modeling of RAGE interaction interfaces with Aβ indicates which chemical compounds can potentially be capable of blocking this interaction, and impair the associated pathogenic cascades. The ability of three RAGE inhibitors (RAP, FPS-ZM1 and RP-1) to disrupt the RAGE:Aβ interaction has been probed by docking and subsequently the complexes’ stability verified by MD. The RP-1 and Aβ interaction areas coincide and therefore this inhibitor is very promising for the RAGE:Aβ interaction inhibition. MDPI 2022-10-05 /pmc/articles/PMC9570301/ /pubmed/36233130 http://dx.doi.org/10.3390/ijms231911816 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Tolstova, Anna P. Adzhubei, Alexei A. Mitkevich, Vladimir A. Petrushanko, Irina Yu. Makarov, Alexander A. Docking and Molecular Dynamics-Based Identification of Interaction between Various Beta-Amyloid Isoforms and RAGE Receptor |
title | Docking and Molecular Dynamics-Based Identification of Interaction between Various Beta-Amyloid Isoforms and RAGE Receptor |
title_full | Docking and Molecular Dynamics-Based Identification of Interaction between Various Beta-Amyloid Isoforms and RAGE Receptor |
title_fullStr | Docking and Molecular Dynamics-Based Identification of Interaction between Various Beta-Amyloid Isoforms and RAGE Receptor |
title_full_unstemmed | Docking and Molecular Dynamics-Based Identification of Interaction between Various Beta-Amyloid Isoforms and RAGE Receptor |
title_short | Docking and Molecular Dynamics-Based Identification of Interaction between Various Beta-Amyloid Isoforms and RAGE Receptor |
title_sort | docking and molecular dynamics-based identification of interaction between various beta-amyloid isoforms and rage receptor |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9570301/ https://www.ncbi.nlm.nih.gov/pubmed/36233130 http://dx.doi.org/10.3390/ijms231911816 |
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