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Protein Predictive Modeling and Simulation of Mutations of Presenilin-1 Familial Alzheimer’s Disease on the Orthosteric Site

Alzheimer’s disease pathology is characterized by β-amyloid plaques and neurofibrillary tangles. Amyloid precursor protein is processed by β and γ secretase, resulting in the production of β-amyloid peptides with a length ranging from 38 to 43 amino acids. Presenilin 1 (PS1) is the catalytic unit of...

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Autores principales: Soto-Ospina, Alejandro, Araque Marín, Pedronel, Bedoya, Gabriel, Sepulveda-Falla, Diego, Villegas Lanau, Andrés
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8206637/
https://www.ncbi.nlm.nih.gov/pubmed/34150846
http://dx.doi.org/10.3389/fmolb.2021.649990
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author Soto-Ospina, Alejandro
Araque Marín, Pedronel
Bedoya, Gabriel
Sepulveda-Falla, Diego
Villegas Lanau, Andrés
author_facet Soto-Ospina, Alejandro
Araque Marín, Pedronel
Bedoya, Gabriel
Sepulveda-Falla, Diego
Villegas Lanau, Andrés
author_sort Soto-Ospina, Alejandro
collection PubMed
description Alzheimer’s disease pathology is characterized by β-amyloid plaques and neurofibrillary tangles. Amyloid precursor protein is processed by β and γ secretase, resulting in the production of β-amyloid peptides with a length ranging from 38 to 43 amino acids. Presenilin 1 (PS1) is the catalytic unit of γ-secretase, and more than 200 PS1 pathogenic mutations have been identified as causative for Alzheimer’s disease. A complete monocrystal structure of PS1 has not been determined so far due to the presence of two flexible domains. We have developed a complete structural model of PS1 using a computational approach with structure prediction software. Missing fragments Met1-Glut72 and Ser290-Glu375 were modeled and validated by their energetic and stereochemical characteristics. Then, with the complete structure of PS1, we defined that these fragments do not have a direct effect in the structure of the pore. Next, we used our hypothetical model for the analysis of the functional effects of PS1 mutations Ala246GLu, Leu248Pro, Leu248Arg, Leu250Val, Tyr256Ser, Ala260Val, and Val261Phe, localized in the catalytic pore. For this, we used a quantum mechanics/molecular mechanics (QM/MM) hybrid method, evaluating modifications in the topology, potential surface density, and electrostatic potential map of mutated PS1 proteins. We found that each mutation exerts changes resulting in structural modifications of the active site and in the shape of the pore. We suggest this as a valid approach for functional studies of PS1 in view of the possible impact in substrate processing and for the design of targeted therapeutic strategies.
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spelling pubmed-82066372021-06-17 Protein Predictive Modeling and Simulation of Mutations of Presenilin-1 Familial Alzheimer’s Disease on the Orthosteric Site Soto-Ospina, Alejandro Araque Marín, Pedronel Bedoya, Gabriel Sepulveda-Falla, Diego Villegas Lanau, Andrés Front Mol Biosci Molecular Biosciences Alzheimer’s disease pathology is characterized by β-amyloid plaques and neurofibrillary tangles. Amyloid precursor protein is processed by β and γ secretase, resulting in the production of β-amyloid peptides with a length ranging from 38 to 43 amino acids. Presenilin 1 (PS1) is the catalytic unit of γ-secretase, and more than 200 PS1 pathogenic mutations have been identified as causative for Alzheimer’s disease. A complete monocrystal structure of PS1 has not been determined so far due to the presence of two flexible domains. We have developed a complete structural model of PS1 using a computational approach with structure prediction software. Missing fragments Met1-Glut72 and Ser290-Glu375 were modeled and validated by their energetic and stereochemical characteristics. Then, with the complete structure of PS1, we defined that these fragments do not have a direct effect in the structure of the pore. Next, we used our hypothetical model for the analysis of the functional effects of PS1 mutations Ala246GLu, Leu248Pro, Leu248Arg, Leu250Val, Tyr256Ser, Ala260Val, and Val261Phe, localized in the catalytic pore. For this, we used a quantum mechanics/molecular mechanics (QM/MM) hybrid method, evaluating modifications in the topology, potential surface density, and electrostatic potential map of mutated PS1 proteins. We found that each mutation exerts changes resulting in structural modifications of the active site and in the shape of the pore. We suggest this as a valid approach for functional studies of PS1 in view of the possible impact in substrate processing and for the design of targeted therapeutic strategies. Frontiers Media S.A. 2021-06-02 /pmc/articles/PMC8206637/ /pubmed/34150846 http://dx.doi.org/10.3389/fmolb.2021.649990 Text en Copyright © 2021 Soto-Ospina, Araque Marín, Bedoya, Sepulveda-Falla and Villegas Lanau. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Molecular Biosciences
Soto-Ospina, Alejandro
Araque Marín, Pedronel
Bedoya, Gabriel
Sepulveda-Falla, Diego
Villegas Lanau, Andrés
Protein Predictive Modeling and Simulation of Mutations of Presenilin-1 Familial Alzheimer’s Disease on the Orthosteric Site
title Protein Predictive Modeling and Simulation of Mutations of Presenilin-1 Familial Alzheimer’s Disease on the Orthosteric Site
title_full Protein Predictive Modeling and Simulation of Mutations of Presenilin-1 Familial Alzheimer’s Disease on the Orthosteric Site
title_fullStr Protein Predictive Modeling and Simulation of Mutations of Presenilin-1 Familial Alzheimer’s Disease on the Orthosteric Site
title_full_unstemmed Protein Predictive Modeling and Simulation of Mutations of Presenilin-1 Familial Alzheimer’s Disease on the Orthosteric Site
title_short Protein Predictive Modeling and Simulation of Mutations of Presenilin-1 Familial Alzheimer’s Disease on the Orthosteric Site
title_sort protein predictive modeling and simulation of mutations of presenilin-1 familial alzheimer’s disease on the orthosteric site
topic Molecular Biosciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8206637/
https://www.ncbi.nlm.nih.gov/pubmed/34150846
http://dx.doi.org/10.3389/fmolb.2021.649990
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