Estudio de la variabilidad genética y la interacción molecular de la proteína Spike de SARS-CoV-2 y la proteína ACE2 humana

ilustraciones, gráficas, tablas

Autores:: Rodriguez Osorio, Jenny Alejandra

Tipo de recurso:

Fecha de publicación:: 2021

Institución:: Universidad Nacional de Colombia

Repositorio:: Universidad Nacional de Colombia

Idioma:: spa

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network_acronym_str	UNACIONAL2
network_name_str	Universidad Nacional de Colombia
repository_id_str
dc.title.spa.fl_str_mv	Estudio de la variabilidad genética y la interacción molecular de la proteína Spike de SARS-CoV-2 y la proteína ACE2 humana
dc.title.translated.eng.fl_str_mv	Study of the genetic variability and molecular interaction of the Spike protein of SARS-CoV-2 and the human ACE2 protein
title	Estudio de la variabilidad genética y la interacción molecular de la proteína Spike de SARS-CoV-2 y la proteína ACE2 humana
spellingShingle	Estudio de la variabilidad genética y la interacción molecular de la proteína Spike de SARS-CoV-2 y la proteína ACE2 humana 570 - Biología::572 - Bioquímica Receptors, Virus Coronavirus Infections Receptores Virales Infecciones por Coronavirus Viral proteins Proteínas virales Bioquímica Receptor ACE2 Proteína Spike de SARS-CoV-2 Acoplamiento molecular Interacción proteína-proteína Mutaciones Variantes del SARS-CoV-2 Biochemistry ACE2 receptor SARS-CoV-2 spike protein Docking Molecular Protein-protein interaction Mutations SARS-CoV-2 variants Mutación Mutation
title_short	Estudio de la variabilidad genética y la interacción molecular de la proteína Spike de SARS-CoV-2 y la proteína ACE2 humana
title_full	Estudio de la variabilidad genética y la interacción molecular de la proteína Spike de SARS-CoV-2 y la proteína ACE2 humana
title_fullStr	Estudio de la variabilidad genética y la interacción molecular de la proteína Spike de SARS-CoV-2 y la proteína ACE2 humana
title_full_unstemmed	Estudio de la variabilidad genética y la interacción molecular de la proteína Spike de SARS-CoV-2 y la proteína ACE2 humana
title_sort	Estudio de la variabilidad genética y la interacción molecular de la proteína Spike de SARS-CoV-2 y la proteína ACE2 humana
dc.creator.fl_str_mv	Rodriguez Osorio, Jenny Alejandra
dc.contributor.advisor.spa.fl_str_mv	Pinzón Velasco, Andrés Mauricio Arboleda Bustos, Carlos Eduardo
dc.contributor.author.spa.fl_str_mv	Rodriguez Osorio, Jenny Alejandra
dc.subject.ddc.spa.fl_str_mv	570 - Biología::572 - Bioquímica
topic	570 - Biología::572 - Bioquímica Receptors, Virus Coronavirus Infections Receptores Virales Infecciones por Coronavirus Viral proteins Proteínas virales Bioquímica Receptor ACE2 Proteína Spike de SARS-CoV-2 Acoplamiento molecular Interacción proteína-proteína Mutaciones Variantes del SARS-CoV-2 Biochemistry ACE2 receptor SARS-CoV-2 spike protein Docking Molecular Protein-protein interaction Mutations SARS-CoV-2 variants Mutación Mutation
dc.subject.decs.eng.fl_str_mv	Receptors, Virus Coronavirus Infections
dc.subject.decs.spa.fl_str_mv	Receptores Virales Infecciones por Coronavirus
dc.subject.lemb.eng.fl_str_mv	Viral proteins
dc.subject.lemb.spa.fl_str_mv	Proteínas virales
dc.subject.proposal.spa.fl_str_mv	Bioquímica Receptor ACE2 Proteína Spike de SARS-CoV-2 Acoplamiento molecular Interacción proteína-proteína Mutaciones Variantes del SARS-CoV-2
dc.subject.proposal.eng.fl_str_mv	Biochemistry ACE2 receptor SARS-CoV-2 spike protein Docking Molecular Protein-protein interaction Mutations SARS-CoV-2 variants
dc.subject.unesco.spa.fl_str_mv	Mutación
dc.subject.unesco.eng.fl_str_mv	Mutation
description	ilustraciones, gráficas, tablas
publishDate	2021
dc.date.issued.none.fl_str_mv	2021-12
dc.date.accessioned.none.fl_str_mv	2022-06-08T18:23:35Z
dc.date.available.none.fl_str_mv	2022-06-08T18:23:35Z
dc.type.spa.fl_str_mv	Trabajo de grado - Maestría
dc.type.driver.spa.fl_str_mv	info:eu-repo/semantics/masterThesis
dc.type.version.spa.fl_str_mv	info:eu-repo/semantics/acceptedVersion
dc.type.content.spa.fl_str_mv	Text
dc.type.redcol.spa.fl_str_mv	http://purl.org/redcol/resource_type/TM
status_str	acceptedVersion
dc.identifier.uri.none.fl_str_mv	https://repositorio.unal.edu.co/handle/unal/81536
dc.identifier.instname.spa.fl_str_mv	Universidad Nacional de Colombia
dc.identifier.reponame.spa.fl_str_mv	Repositorio Institucional Universidad Nacional de Colombia
dc.identifier.repourl.spa.fl_str_mv	https://repositorio.unal.edu.co/
url	https://repositorio.unal.edu.co/handle/unal/81536 https://repositorio.unal.edu.co/
identifier_str_mv	Universidad Nacional de Colombia Repositorio Institucional Universidad Nacional de Colombia
dc.language.iso.spa.fl_str_mv	spa
language	spa
dc.relation.indexed.spa.fl_str_mv	Bireme
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dc.publisher.department.spa.fl_str_mv	Departamento de Química
dc.publisher.faculty.spa.fl_str_mv	Facultad de Ciencias
dc.publisher.place.spa.fl_str_mv	Bogotá, Colombia
dc.publisher.branch.spa.fl_str_mv	Universidad Nacional de Colombia - Sede Bogotá
institution	Universidad Nacional de Colombia
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spelling	Reconocimiento 4.0 Internacionalhttp://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccesshttp://purl.org/coar/access_right/c_abf2Pinzón Velasco, Andrés Mauricio366c2eddf6aa24434ee55e57da235448Arboleda Bustos, Carlos Eduardo1b40af3328ad09fee0f9bf17bdfa1f30600Rodriguez Osorio, Jenny Alejandrafbc51f34a8484eaa85f0c93261bd29d76002022-06-08T18:23:35Z2022-06-08T18:23:35Z2021-12https://repositorio.unal.edu.co/handle/unal/81536Universidad Nacional de ColombiaRepositorio Institucional Universidad Nacional de Colombiahttps://repositorio.unal.edu.co/ilustraciones, gráficas, tablasLas interacciones entre la enzima convertidora de angiotensina humana 2 (ACE2) y la región del dominio de unión al receptor (RBD) de la proteína Spike del SARS-CoV-2 son críticas para la entrada del virus en la célula huésped. El objetivo de este trabajo fue identificar algunas de las variantes más relevantes de la proteína Spike de SARS-CoV-2 que surgieron durante la pandemia y evaluar su afinidad de unión con variantes de la proteína ACE2 humana. En este trabajo se empleó el acoplamiento molecular (docking molecular) para predecir los efectos de cinco mutaciones de ACE2 en interacción con mutaciones específicas en la región RBD de la proteína Spike de SARS-CoV-2 que se originaron en el Reino Unido (N501Y) variante Alfa, Sudáfrica (K417N ‐ E484K ‐ N501Y) variante Beta, India (L452R-T478K) variante Delta y una variante hipotética (E484K). Nuestros resultados sugieren que, en conjunto, estas variantes alteran la interacción entre las proteínas Spike y ACE2, perdiendo o creando interacciones intermoleculares, mejorando la aptitud viral al mejorar la afinidad de unión y conduciendo a un aumento de la infectividad y transmisión. Destacamos que la mutación S19P de ACE2 disminuye la afinidad de unión entre las proteínas ACE2 y Spike en presencia de la variante Beta y la variante tipo salvaje o wild type del SARS-CoV-2 aislado en Wuhan-2019. La mutación R115Q de ACE2 baja la afinidad unión de estas dos proteínas en presencia de las variantes Beta y Delta. De igual manera, K26R baja la afinidad de interacción entre las proteínas ACE2 y Spike en presencia de la variante Alfa. Esta disminución en la afinidad de unión probablemente se deba a la falta de interacción entre algunos de los residuos claves del complejo de interacción entre la proteína ACE2 y la región RBD de la proteína Spike de SARS-CoV-2. Por lo tanto, las mutaciones de ACE2 mencionadas en presencia de estas variantes, podrían sugerir una resistencia intrínseca ante la enfermedad del COVID-19. Por otro lado, nuestros resultados sugieren que las mutaciones K26R, M332L y K341R de ACE2 aumentan expresivamente la afinidad entre las proteínas ACE2 y Spike en las variantes Alfa, Beta y Delta. En consecuencia, estas mutaciones de ACE2 en presencia de las variantes Alfa, Beta y delta del SARS-CoV-2 podrían ser más infecciosos en células humanas en comparación con el SARS-CoV-2 aislado en Wuhan-2019. (Texto tomado de la fuente).Interactions between the human angiotensin-converting enzyme 2 (ACE2) and the RBD region of the SARS-CoV-2 Spike protein are critical for virus entry into the host cell. The objective of this work is to identify some of the most relevant SARS-CoV-2 spike variants that emerged during the pandemic and evaluate their binding affinity with human variants of ACE2. We used molecular docking to predict the effects of five mutations of ACE2 when they interact with the specific mutations that originated in the UK (N501Y) Alpha variant, South Africa (K417N - E484K - N501Y) Beta variant, India (L452R-T478K) Delta variant, and a hypothetical variant (E484K) in the RBD region of the Spike protein of SARS-CoV-2. Our results suggest that together, these variants alter the interaction of the Spike and the human ACE2 protein, losing or creating new inter-protein contacts, enhancing viral fitness by improving binding affinity, and leading to an increase in infectivity and transmission. This investigation highlighted that the ACE2 S19P mutation decreases the binding affinity between the ACE2 and Spike proteins in the presence of the Beta variant and the wild-type variant of SARS-CoV-2 isolated in Wuhan-2019. The R115Q mutation of ACE2 lowers the binding affinity of these two proteins in the presence of the Beta and Delta variants. Similarly, K26R lowers the affinity of the interaction between the ACE2 and Spike proteins in the presence of the Alpha variant. This decrease in binding affinity is probably due to the lack of interaction between some of the key residues of the interaction complex between the ACE2 protein and the RBD region of the SARS-CoV-2 Spike protein. Therefore, ACE2 mutations appear in the presence of these variants, they could suggest an intrinsic resistance to COVID-19 disease. On the other hand, our results suggested that the K26R, M332L, and K341R mutations of ACE2 expressively showed the affinity between the ACE2 and Spike proteins in the Alpha, Beta, and Delta variants. Consequently, these ACE2 mutations in the presence of the Alpha, Beta, and delta variants of SARS-CoV-2 could be more infectious in human cells compared to the SARS-CoV-2 isolated in Wuhan-2019.Incluye anexosMaestríaMagíster en Ciencias - Bioquímica1. Minería de datos para estructura y polimorfismo genético del gen ACE2. La variabilidad genética a lo largo de la región del gen ACE2 para las diferentes poblaciones analizadas se obtuvo a partir del uso de la herramienta Data Slicer (https://www.ensembl.org/Homo_sapiens/Tools/DataSlicer) implementada en el Ensembl Genome Browser (https://www.ensembl.org) (Karczewski et al. 2020). Las bases de datos de dbSNP (https://www.ncbi.nlm.nih.gov/snp), gnomAD (https://gnomad.broadinstitute.org) y Ensembl Genome Browser (Yates et al. 2020) fueron empleadas para determinar las frecuencias alélicas de los SNPs identificados en la región ACE2. Para ello se tomaron las regiones de los 18 exones del gen ACE2 y se evaluó la variabilidad genética en las poblaciones americanas (AMR) que incluye población proveniente de Colombia (CLM), California (MXL), Perú (PEL) y Puerto Rico (PUR). En poblaciones africanas (AFR) que incluyen población proveniente de Barbados (ACB), Ascendencia africana en el suroeste de US (ASW), Esan Nigeria (ESN), Gambia (GWD), Kenya (LWK), Yoruba en Ibadan Nigeria (YRI) y Mende en Sierra Leona (MSL). Poblaciones europeas (EUR) que incluyen Residentes de Utah con ascendencia de Europa del Norte y Occidental (CEU), Finlandia (FIN), Británicos en Inglaterra y Escocia (GBR), Poblaciones ibéricas en España (IBS) y Toscani en Italia (TSI). Poblaciones del este de Asia (EAS) que incluyen Dai chino en Xishuangbanna, China (CDX), China Han en Bejing, China (CHB), China Han del Sur, China (CHS), Japonés en Tokio, Japón (JPT) y Kinh en Ciudad Ho Chi Minh, Vietnam (KHV). Finalmente se emplearon datos de poblaciones del sur de Asia (SAS) que incluyen Bengalí en Bangladesh (BAB), India gujarati en Houston, TX (GIH), Telugu indio en el Reino Unido (UIT), Punjabi en Lahore, Pakistán (PJL) y Tamil de Sri Lanka en el Reino Unido (STU). 2. Análisis del impacto de las mutaciones no sinónimas. El efecto de la sustitución de aminoácidos en las proteínas ACE2 humano y Spike de SARS-CoV2 sobre la estabilidad de la proteína se predijo a 37 ° C y pH: 7 utilizando i-Stable Server (Chen, Lin, and Chu 2013) y CUPSAT (Cologne University Protein Stability Analysis Tool) (Parthiban, Gromiha, and Schomburg 2006). Se aplicó el servidor i-Stable para predecir las alteraciones de estabilidad por las variantes seleccionadas en cada proteína. i-Stable Server proporciona resultados de los programas I-Mutant2.0 (Capriotti, Fariselli, and Casadio 2005) y MUpro (Cheng, Randall, and Baldi 2006) prediciendo en meta resultados. El programa define la estabilidad de una proteína como valor positivo (+) por una diferencia de energía libre (ΔΔG) > 0, una puntuación superior a 0 pronostica una mayor estabilidad y los datos negativos (-) como desestabilizadores, un valor de ΔΔG <0 indica una disminución en la estabilidad de la estructura. El programa también predice la distribución de datos basándose en la estructura secundaria y la accesibilidad relativa al solvente (RSA) del sitio de mutación. Los rangos que determinan el RSA son los siguientes: valores inferiores al 10% como superficie inferior, valores entre 10% y 20% son clasificados como enterrados, valores entre 20% ~ 50% como parcialmente enterrados y finalmente, valores entre 50% y 100% como expuestos. La puntuación de confianza de i-Stable varía entre 0 y 1, donde el valor más alto expone una mayor confianza. (Chen, Lin, and Chu 2013). El programa CUPSAT utiliza específicos átomos potenciales del entorno estructural y ángulos de torsión potenciales para predecir energía libre (ΔΔG) de la estructura en cuestión. La diferencia en la energía libre se compara entre proteínas wild-type y mutantes. El resultado consta de información sobre el sitio de la mutación, sus características estructurales (accesibilidad al disolvente y ángulos de torsión) e información completa sobre los cambios en la estabilidad de las proteínas (Parthiban, Gromiha, and Schomburg 2006). En el método de cálculo de energía libre, la diferencia de energía libre, ΔΔG, se calcula como una diferencia ΔΔG = ΔGN - ΔGD , donde ΔGN y ΔGD se definen como el cambio de energía libre de la estructura tipo wild-type a la estructura mutante en el estado nativo y en el estado desnaturalizado, respectivamente. (Funahashi et al. 2003). Finalmente, se empleó la herramienta bioinformática HOPE (Venselaar et al. 2010). HOPE es un programa que analiza los efectos estructurales y funcionales de las mutaciones puntuales, recopilando información de una amplia gama de fuentes de información, incluidos cálculos sobre las coordenadas 3D de la proteína mediante el uso de servicios web WHAT IF, anotaciones de secuencia de la base de datos UniProt y predicciones de los servicios DAS. Los modelos de homología se construyen con YASARA (Venselaar et al. 2010). 3. Preparación del sistema y Docking Molecular. Los modelos estructurales de las variantes seleccionadas del SARS-CoV-2 y las mutaciones no sinónimas del receptor ACE2 se diseñaron empleando como plantilla la estructura cristalina PDB ID: 6M0J que involucra la región RBD de la proteína S de SARS-CoV-2 y a la proteína ACE2 humana (Lan et al. 2020). El ion cloruro, el ion zinc, los glicanos y las moléculas de agua de la estructura cristalina se mantuvieron en sus posiciones originales. Se realizó la minimización de la energía del complejo proteico original utilizando el programa YASARA (www.yasara.org)(Krieger, Koraimann, and Vriend 2002), mediante el algoritmo “Steepest descent minimization” (simulation > temperature control > steepest descent minimization). Los nuevos archivos generados se exportaron en formato PDB y se visualizaron directamente en PyMOL Molecular Graphics System, Versión 1.8 (Schrödinger 2015), para luego generar los complejos mutantes. El acople de las estructuras se llevó a cabo con el servidor HDOCK (http://hdock.phys.hust.edu.cn/) (Yan et al. 2020). El servidor predice automáticamente la interacción proteína-proteína a través de un algoritmo híbrido de acoplamiento basado en plantillas y sin plantillas o ab initio. La desviación cuadrática media (RMSD) se estimó para cada modelo. Se empleó el servidor QMEANDisCo SwissDock (Studer et al. 2020) para validar los complejos formados por HDOCK, debido a que emplea métricas de malos enlaces y ángulos. QMEANDisCo es un método de estimación de calidad predeterminado empleado por el servidor de modelado de homología SWISS-MODEL. Es una puntuación compuesta que se basa en una combinación de términos basados en el conocimiento y una nueva puntuación de restricción de distancia (DisCo). DisCo evalúa la concordancia entre las distancias observadas por pares en un modelo con un conjunto de restricciones extraídas de estructuras determinadas experimentalmente que son homólogas al modelo que se está evaluando (Studer et al. 2020). 4. Análisis estructurales de los complejos ACE2/Spike. Los resultados de las simulaciones realizadas en HDOCK se confirmaron mediante el envío de complejos ACE2/Spike generados por HDOCK a PRODIGY. PRODIGY (protein binding energy prediction), es una herramienta en línea para la predicción de la afinidad de unión en complejos proteína-proteína. (Xue et al. 2016). La afinidad de enlace es la fuerza de unión ligando-receptor. Esta afinidad determina si un ligando finalmente se unirá o se separará de la superficie del receptor y volverá a su estado libre. Los resultados del servidor PRODIGY incluyen: el valor previsto de la energía libre de enlace (ΔG) en kcal mol -1 ; el valor predicho de la constante de disociación (KD) en M calculado a partir de ΔG = RT ln (KD), donde R es la constante de gas idea (kcal K −1 mol −1 ), T es la temperatura (K), en nuestro estudio tomamos una temperatura de 37°C, y finalmente el número y tipo de interacciones intermoleculares dentro del límite de distancia de 5,5 Å. Es importante mencionar que PRODIGY no predice la distancia exacta de las interacciones entre los residuos, sino que predice qué interacciones se están formando a una distancia inferior a 5,5 Å. Más, sin embargo, el servidor HDOCK si proporciona estas distancias, no obstante, HDOCK sólo predice interacciones con distancias inferiores a 5 Å. Por lo tanto, se implementaron ambas herramientas para construir la tabla de interacciones entre los residuos de ACE2 y Spike para los complejos desarrollados. Las distancias superiores a 5 Å se denominaron como (NN) indicando que sí hay interacción y que la interacción presenta una distancia entre 5 – 5.5 Å.99 páginasapplication/pdfapplication/vnd.ms-excelspaUniversidad Nacional de ColombiaBogotá - Ciencias - Maestría en Ciencias - BioquímicaDepartamento de QuímicaFacultad de CienciasBogotá, ColombiaUniversidad Nacional de Colombia - Sede Bogotá570 - Biología::572 - BioquímicaReceptors, VirusCoronavirus InfectionsReceptores ViralesInfecciones por CoronavirusViral proteinsProteínas viralesBioquímicaReceptor ACE2Proteína Spike de SARS-CoV-2Acoplamiento molecularInteracción proteína-proteínaMutacionesVariantes del SARS-CoV-2BiochemistryACE2 receptorSARS-CoV-2 spike proteinDocking MolecularProtein-protein interactionMutationsSARS-CoV-2 variantsMutaciónMutationEstudio de la variabilidad genética y la interacción molecular de la proteína Spike de SARS-CoV-2 y la proteína ACE2 humanaStudy of the genetic variability and molecular interaction of the Spike protein of SARS-CoV-2 and the human ACE2 proteinTrabajo de grado - Maestríainfo:eu-repo/semantics/masterThesisinfo:eu-repo/semantics/acceptedVersionTexthttp://purl.org/redcol/resource_type/TMBiremeAbd El-Aziz, Tarek Mohamed, Ahmed Al-Sabi, and James D. Stockand. 2020. “Human Recombinant Soluble ACE2 (HrsACE2) Shows Promise for Treating Severe COVID19.” Signal Transduction and Targeted Therapy 5 (1): 3–4. https://doi.org/10.1038/s41392-020-00374-6.Al-Mulla, Fahd, Anwar Mohammad, Ashraf Al Madhoun, Dania Haddad, Hamad Ali, Muthukrishnan Eaaswarkhanth, Sumi Elsa John, et al. 2021. “ACE2 and FURIN Variants Are Potential Predictors of SARS-CoV-2 Outcome: A Time to Implement Precision Medicine against COVID-19.” Heliyon 7 (2): e06133. https://doi.org/10.1016/j.heliyon.2021.e06133.Alanagreh, Lo’Ai, Foad Alzoughool, and Manar Atoum. 2020. “The Human Coronavirus Disease Covid-19: Its Origin, Characteristics, and Insights into Potential Drugs and Its Mechanisms.” Pathogens 9 (5). https://doi.org/10.3390/pathogens9050331.Aleem, Abdul, Abdul Bari Akbar Samad, and Amy K Slenker. 2021. “Emerging Variants of SARS-CoV-2 And Novel Therapeutics Against Coronavirus (COVID-19).” In . 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ColombiaEstudiantesInvestigadoresMaestrosMedios de comunicaciónPúblico generalORIGINAL1032472021.2021.pdf1032472021.2021.pdfTesis de Maestría en Ciencias - Bioquímicaapplication/pdf2777350https://repositorio.unal.edu.co/bitstream/unal/81536/1/1032472021.2021.pdfd30269bf3e468a1df7ec5b15d59dffc4MD51Tabla complementaria 1 Variantes identificadas en el gen ACE2 presentes en las bases de datos GnomAD y Ensembl..pdfTabla complementaria 1 Variantes identificadas en el gen ACE2 presentes en las bases de datos GnomAD y Ensembl..pdfAnexo 1application/pdf156752https://repositorio.unal.edu.co/bitstream/unal/81536/3/Tabla%20complementaria%201%20Variantes%20identificadas%20en%20el%20gen%20ACE2%20presentes%20en%20las%20bases%20de%20datos%20GnomAD%20y%20Ensembl..pdf7b003319f4e320f7f052c82439c60631MD53Tabla complementaria 2 Interacciones intermoleculares entre los complejos ACE2-RBD-Spike predichas por los servidores HDOCK y Prodigy.xlsxTabla complementaria 2 Interacciones intermoleculares entre los 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Estudio de la variabilidad genética y la interacción molecular de la proteína Spike de SARS-CoV-2 y la proteína ACE2 humana

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