Molecular dynamics simulations of Alzheimer's BACE1 and BACE2 transmembrane domains in neurons: Impact of cholesterol
ABSTRACT : Molecular dynamic (MD) simulation is an approach frequently employed in computational biology for exhaustive sampling of the protein-ligand conformational space. Hence, it is useful for structural analysis and the study of molecular interactions. In this study, we report on a MD simulatio...
- Autores:
-
Cruz Jiménez, Juan Carlos
Mercado Montoya, Marcela
Ostos Ortíz, Carlos Eduardo
Hernández Validivieso, Alher Mauricio
- Tipo de recurso:
- Article of investigation
- Fecha de publicación:
- 2021
- Institución:
- Universidad de Antioquia
- Repositorio:
- Repositorio UdeA
- Idioma:
- eng
- OAI Identifier:
- oai:bibliotecadigital.udea.edu.co:10495/24961
- Acceso en línea:
- http://hdl.handle.net/10495/24961
https://revistas.udea.edu.co/index.php/ingenieria/article/view/332882
- Palabra clave:
- Enfermedad de Alzheimer
Alzheimer Disease
Colesterol
Cholesterol
Análisis modal
Modos complejos
Análisis estructural
Interacción molecular
- Rights
- openAccess
- License
- http://creativecommons.org/licenses/by-nc-sa/2.5/co/
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| dc.title.spa.fl_str_mv |
Molecular dynamics simulations of Alzheimer's BACE1 and BACE2 transmembrane domains in neurons: Impact of cholesterol |
| dc.title.alternative.spa.fl_str_mv |
Simulaciones de dinámica molecular de dominios transmembranales de BACE1 y BACE2 del Alzheimer en neuronas: Impacto del colesterol |
| title |
Molecular dynamics simulations of Alzheimer's BACE1 and BACE2 transmembrane domains in neurons: Impact of cholesterol |
| spellingShingle |
Molecular dynamics simulations of Alzheimer's BACE1 and BACE2 transmembrane domains in neurons: Impact of cholesterol Enfermedad de Alzheimer Alzheimer Disease Colesterol Cholesterol Análisis modal Modos complejos Análisis estructural Interacción molecular |
| title_short |
Molecular dynamics simulations of Alzheimer's BACE1 and BACE2 transmembrane domains in neurons: Impact of cholesterol |
| title_full |
Molecular dynamics simulations of Alzheimer's BACE1 and BACE2 transmembrane domains in neurons: Impact of cholesterol |
| title_fullStr |
Molecular dynamics simulations of Alzheimer's BACE1 and BACE2 transmembrane domains in neurons: Impact of cholesterol |
| title_full_unstemmed |
Molecular dynamics simulations of Alzheimer's BACE1 and BACE2 transmembrane domains in neurons: Impact of cholesterol |
| title_sort |
Molecular dynamics simulations of Alzheimer's BACE1 and BACE2 transmembrane domains in neurons: Impact of cholesterol |
| dc.creator.fl_str_mv |
Cruz Jiménez, Juan Carlos Mercado Montoya, Marcela Ostos Ortíz, Carlos Eduardo Hernández Validivieso, Alher Mauricio |
| dc.contributor.author.none.fl_str_mv |
Cruz Jiménez, Juan Carlos Mercado Montoya, Marcela Ostos Ortíz, Carlos Eduardo Hernández Validivieso, Alher Mauricio |
| dc.subject.decs.none.fl_str_mv |
Enfermedad de Alzheimer Alzheimer Disease Colesterol Cholesterol |
| topic |
Enfermedad de Alzheimer Alzheimer Disease Colesterol Cholesterol Análisis modal Modos complejos Análisis estructural Interacción molecular |
| dc.subject.proposal.spa.fl_str_mv |
Análisis modal Modos complejos Análisis estructural Interacción molecular |
| description |
ABSTRACT : Molecular dynamic (MD) simulation is an approach frequently employed in computational biology for exhaustive sampling of the protein-ligand conformational space. Hence, it is useful for structural analysis and the study of molecular interactions. In this study, we report on a MD simulation protocol to understand the dynamics of β-secretase 1 (BACE1) and 2 (BACE2), widely known to play a critical role in the etiology of Alzheimer’s disease, by a structure change evaluation of their transmembrane domains while inserted in a simulated neural membrane system. We considered two different levels in membrane cholesterol content. Because there is no evidence supporting the capacity of BACE1 and BACE2 to exist as a dimer, single and double (BACE1/BACE1, BACE2/BACE2, BACE1/BACE2) systems, either in parallel or antiparallel orientation, were prepared for each run. Analysis of tridimensional structure of BACE1 and BACE2, after 10ns of MD simulation, revealed a correlation between higher cholesterol levels and both peptide refolding and changes in the secondary structure of both transmembrane domains in single and double systems. Interestingly, our results also indicate a potential interaction in the double system BACE2/BACE2, particularly when the domains had an antiparallel orientation. |
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2021 |
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2021-12-10T21:35:23Z |
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2021-12-10T21:35:23Z |
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2021 |
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info:eu-repo/semantics/article |
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http://purl.org/coar/version/c_970fb48d4fbd8a85 |
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Artículo de investigación |
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Cruz-Jiménez J. C., Mercado-Montoya M., Ostos-Ortíz C. E., and Hernández Validivieso A. M., “Molecular dynamics simulations of Alzheimer’s BACE1 and BACE2 transmembrane domains in neurons: Impact of cholesterol”, Rev.Fac.Ing.Univ.Antioquia, no. 98, pp. 117-128, Mar. 2021. |
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0120-6230 |
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http://hdl.handle.net/10495/24961 |
| dc.identifier.doi.none.fl_str_mv |
10.17533/udea.redin.20200368 |
| dc.identifier.eissn.none.fl_str_mv |
2422-2844 |
| dc.identifier.url.spa.fl_str_mv |
https://revistas.udea.edu.co/index.php/ingenieria/article/view/332882 |
| identifier_str_mv |
Cruz-Jiménez J. C., Mercado-Montoya M., Ostos-Ortíz C. E., and Hernández Validivieso A. M., “Molecular dynamics simulations of Alzheimer’s BACE1 and BACE2 transmembrane domains in neurons: Impact of cholesterol”, Rev.Fac.Ing.Univ.Antioquia, no. 98, pp. 117-128, Mar. 2021. 0120-6230 10.17533/udea.redin.20200368 2422-2844 |
| url |
http://hdl.handle.net/10495/24961 https://revistas.udea.edu.co/index.php/ingenieria/article/view/332882 |
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eng |
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eng |
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Rev. Fac. Ing. Univ. Antioquia |
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Universidad de Antioquia, Facultad de Ingeniería |
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Catalizadores y Adsorbentes Grupo de Investigación en Bioinstrumentación e Ingeniería Clínica (GIBIC) |
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Medellín, Colombia |
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Universidad de Antioquia |
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Cruz Jiménez, Juan CarlosMercado Montoya, MarcelaOstos Ortíz, Carlos EduardoHernández Validivieso, Alher Mauricio2021-12-10T21:35:23Z2021-12-10T21:35:23Z2021Cruz-Jiménez J. C., Mercado-Montoya M., Ostos-Ortíz C. E., and Hernández Validivieso A. M., “Molecular dynamics simulations of Alzheimer’s BACE1 and BACE2 transmembrane domains in neurons: Impact of cholesterol”, Rev.Fac.Ing.Univ.Antioquia, no. 98, pp. 117-128, Mar. 2021.0120-6230http://hdl.handle.net/10495/2496110.17533/udea.redin.202003682422-2844https://revistas.udea.edu.co/index.php/ingenieria/article/view/332882ABSTRACT : Molecular dynamic (MD) simulation is an approach frequently employed in computational biology for exhaustive sampling of the protein-ligand conformational space. Hence, it is useful for structural analysis and the study of molecular interactions. In this study, we report on a MD simulation protocol to understand the dynamics of β-secretase 1 (BACE1) and 2 (BACE2), widely known to play a critical role in the etiology of Alzheimer’s disease, by a structure change evaluation of their transmembrane domains while inserted in a simulated neural membrane system. We considered two different levels in membrane cholesterol content. Because there is no evidence supporting the capacity of BACE1 and BACE2 to exist as a dimer, single and double (BACE1/BACE1, BACE2/BACE2, BACE1/BACE2) systems, either in parallel or antiparallel orientation, were prepared for each run. Analysis of tridimensional structure of BACE1 and BACE2, after 10ns of MD simulation, revealed a correlation between higher cholesterol levels and both peptide refolding and changes in the secondary structure of both transmembrane domains in single and double systems. Interestingly, our results also indicate a potential interaction in the double system BACE2/BACE2, particularly when the domains had an antiparallel orientation.RESUMEN : Las simulaciones de dinámica molecular (MD) son una aproximación que se emplea frecuentemente en biología computacional para muestreo exhaustivo del espacio conformacional proteína-ligando. Por este motivo, son útiles para el análisis estructural y el estudio de interacciones moleculares. En este estudio, reportamos sobre el protocolo de simulación MD para entender la dinámica de las β-secretasa 1 (BACE1) y 2 (BACE2), los cuales se sabe ampliamente que juegan un papel transcendental en la enfermedad de Alzheimer. Esto se logró evaluando los cambios estructurales en los dominios a través de la membrana mientras se encontraban insertos en un complejo de membrana neuronal simulada. Aquí se consideraron dos niveles en el contenido de colesterol de la membrana. Debido a que no existe evidencia reportada soportando la capacidad de dimerización de BACE1 y BACE2, se prepararon sistemas sencillos y dobles (BACE1/BACE1, BACE2/BACE2, BACE1/BACE2) tanto en orientación paralela como antiparalela para cada corrida. Después de 10ns de simulación MD, el análisis de la estructura tridimensional reveló una correlación entre los altos niveles de colesterol y tanto el replegamiento de péptidos como los cambios en la estructura secundaria de ambos dominios transmembranales en sistemas simples y dobles. Interesantemente, nuestros resultados también indican un marcado potencial de interacción en el Sistema doble BACE2/BACE2, particularmente cuando los dominios asumen una orientación antiparalela.COL0054963COL000192312application/pdfengUniversidad de Antioquia, Facultad de IngenieríaCatalizadores y AdsorbentesGrupo de Investigación en Bioinstrumentación e Ingeniería Clínica (GIBIC)Medellín, Colombiainfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_2df8fbb1https://purl.org/redcol/resource_type/ARTArtículo de investigaciónhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/openAccesshttp://creativecommons.org/licenses/by-nc-sa/2.5/co/http://purl.org/coar/access_right/c_abf2https://creativecommons.org/licenses/by-nc-sa/4.0/Molecular dynamics simulations of Alzheimer's BACE1 and BACE2 transmembrane domains in neurons: Impact of cholesterolSimulaciones de dinámica molecular de dominios transmembranales de BACE1 y BACE2 del Alzheimer en neuronas: Impacto del colesterolEnfermedad de AlzheimerAlzheimer DiseaseColesterolCholesterolAnálisis modalModos complejosAnálisis estructuralInteracción molecularRev. Fac. Ing. Univ. AntioquiaRevista Facultad de Ingeniería Universidad de Antioquia11712898ORIGINALCruzJuan_2021_MolecularDynamicsSimulations.pdfCruzJuan_2021_MolecularDynamicsSimulations.pdfArtículo de investigaciónapplication/pdf785559https://bibliotecadigital.udea.edu.co/bitstream/10495/24961/1/CruzJuan_2021_MolecularDynamicsSimulations.pdff486ba906f21e5c1d9a76b2863b92766MD51CC-LICENSElicense_rdflicense_rdfapplication/rdf+xml; charset=utf-81051https://bibliotecadigital.udea.edu.co/bitstream/10495/24961/2/license_rdfe2060682c9c70d4d30c83c51448f4eedMD52LICENSElicense.txtlicense.txttext/plain; charset=utf-81748https://bibliotecadigital.udea.edu.co/bitstream/10495/24961/3/license.txt8a4605be74aa9ea9d79846c1fba20a33MD5310495/24961oai:bibliotecadigital.udea.edu.co:10495/249612023-08-04 14:47:50.083Repositorio Institucional Universidad de Antioquiaandres.perez@udea.edu.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 |