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1. The structural role of SARS-CoV-2 genetic background in the emergence and success of spike mutations: The case of the spike A222V mutation

Author

European Commission, Consejo Superior de Investigaciones Científicas (España), Ministerio de Ciencia e Innovación (España), Generalitat Valenciana, Comunidad de Madrid, Banco Santander, Instituto de Salud Carlos III, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Ministerio de Economía y Competitividad (España), Ginex, Tiziana [0000-0002-5739-8713], Marco-Marín, Clara [0000-0002-8813-3515], Wieczor, Milosz [0000-0003-4990-8629], Mata, Carlos P. [0000-0003-3381-7431], Krieger, James [0000-0001-6194-6244], Ruiz-Rodríguez, Paula [0000-0003-0727-5974], López-Redondo, Marisa [0000-0002-3328-6821], Francés-Gómez, Clara [0000-0001-7341-3824], Melero, Roberto [0000-0001-9467-9381], Sorzano, Carlos Óscar S. [0000-0002-9473-283X], Martínez, Marta [0000-0002-8435-5540], Gougeard, Nadine [0000-0001-7338-7267], Forcada-Nadal, Alicia [0000-0003-0179-4044], Zamora-Caballero, Sara [0000-0003-4717-8845], Gozalbo-Rovira, Roberto [0000-0003-3427-3800], Sanz-Frasquet, Carla [0000-0002-6990-3131], Arranz, Rocío [0000-0001-5321-0915], Bravo, Jerónimo [0000-0001-6695-2846], Rubio, Vicente [0000-0001-8124-1196], Marina, Alberto [0000-0002-1334-5273], Geller, Ron [0000-0002-7612-4611], Comas, Iñaki [0000-0001-5504-9408], Gil, Carmen [0000-0002-3882-6081], Coscollá, Mireia [0000-0003-0752-0538], Orozco, Modesto [0000-0002-8608-3278], Llácer, José Luis [0000-0001-5304-1795], Carazo, José M. [0000-0003-0788-8447], Ginex, Tiziana, Marco-Marín, Clara, Wieczor, Milosz, Mata, Carlos P., Krieger, James, Ruiz-Rodríguez, Paula, López-Redondo, Marisa, Francés-Gómez, Clara, Melero, Roberto, Sorzano, Carlos Óscar S., Martínez, Marta, Gougeard, Nadine, Forcada-Nadal, Alicia, Zamora-Caballero, Sara, Gozalbo-Rovira, Roberto, Sanz-Frasquet, Carla, Arranz, Rocío, Bravo, Jerónimo, Rubio, Vicente, Marina, Alberto, The IBV-Covid19-Pipeline, Geller, Ron, Comas, Iñaki, Gil, Carmen, Coscollá, Mireia, Orozco, Modesto, Llácer, José Luis, Carazo, José M., European Commission, Consejo Superior de Investigaciones Científicas (España), Ministerio de Ciencia e Innovación (España), Generalitat Valenciana, Comunidad de Madrid, Banco Santander, Instituto de Salud Carlos III, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Ministerio de Economía y Competitividad (España), Ginex, Tiziana [0000-0002-5739-8713], Marco-Marín, Clara [0000-0002-8813-3515], Wieczor, Milosz [0000-0003-4990-8629], Mata, Carlos P. [0000-0003-3381-7431], Krieger, James [0000-0001-6194-6244], Ruiz-Rodríguez, Paula [0000-0003-0727-5974], López-Redondo, Marisa [0000-0002-3328-6821], Francés-Gómez, Clara [0000-0001-7341-3824], Melero, Roberto [0000-0001-9467-9381], Sorzano, Carlos Óscar S. [0000-0002-9473-283X], Martínez, Marta [0000-0002-8435-5540], Gougeard, Nadine [0000-0001-7338-7267], Forcada-Nadal, Alicia [0000-0003-0179-4044], Zamora-Caballero, Sara [0000-0003-4717-8845], Gozalbo-Rovira, Roberto [0000-0003-3427-3800], Sanz-Frasquet, Carla [0000-0002-6990-3131], Arranz, Rocío [0000-0001-5321-0915], Bravo, Jerónimo [0000-0001-6695-2846], Rubio, Vicente [0000-0001-8124-1196], Marina, Alberto [0000-0002-1334-5273], Geller, Ron [0000-0002-7612-4611], Comas, Iñaki [0000-0001-5504-9408], Gil, Carmen [0000-0002-3882-6081], Coscollá, Mireia [0000-0003-0752-0538], Orozco, Modesto [0000-0002-8608-3278], Llácer, José Luis [0000-0001-5304-1795], Carazo, José M. [0000-0003-0788-8447], Ginex, Tiziana, Marco-Marín, Clara, Wieczor, Milosz, Mata, Carlos P., Krieger, James, Ruiz-Rodríguez, Paula, López-Redondo, Marisa, Francés-Gómez, Clara, Melero, Roberto, Sorzano, Carlos Óscar S., Martínez, Marta, Gougeard, Nadine, Forcada-Nadal, Alicia, Zamora-Caballero, Sara, Gozalbo-Rovira, Roberto, Sanz-Frasquet, Carla, Arranz, Rocío, Bravo, Jerónimo, Rubio, Vicente, Marina, Alberto, The IBV-Covid19-Pipeline, Geller, Ron, Comas, Iñaki, Gil, Carmen, Coscollá, Mireia, Orozco, Modesto, Llácer, José Luis, and Carazo, José M.

Abstract

The S:A222V point mutation, within the G clade, was characteristic of the 20E (EU1) SARS-CoV-2 variant identified in Spain in early summer 2020. This mutation has since reappeared in the Delta subvariant AY.4.2, raising questions about its specific effect on viral infection. We report combined serological, functional, structural and computational studies characterizing the impact of this mutation. Our results reveal that S:A222V promotes an increased RBD opening and slightly increases ACE2 binding as compared to the parent S:D614G clade. Finally, S:A222V does not reduce sera neutralization capacity, suggesting it does not affect vaccine effectiveness.

Published
2022

2. The structural role of SARS-CoV-2 genetic background in the emergence and success of spike mutations: the case of the spike A222V mutation

Author

European Commission, Consejo Superior de Investigaciones Científicas (España), Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Comunidad de Madrid, European Research Council, Instituto de Salud Carlos III, Banco Santander, Generalitat Valenciana, Ginex, Tiziana [0000-0002-5739-8713], Marco-Marín, Clara [0000-0002-8813-3515], Wieczor, Milosz [0000-0003-4990-8629], Mata, Carlos P. [0000-0003-3381-7431], Krieger, James [0000-0001-6194-6244], López-Redondo, Marisa [0000-0002-3328-6821], Francés-Gómez, Clara [0000-0001-7341-3824], Ruiz-Rodríguez, Paula [0000-0003-0727-5974], Melero, Roberto [0000-0001-9467-9381], Sorzano, Carlos Óscar S. [0000-0002-9473-283X], Martínez, Marta [0000-0002-8435-5540], Gougeard, Nadine [0000-0001-7338-7267], Forcada-Nadal, Alicia [0000-0003-0179-4044], Zamora-Caballero, Sara [0000-0003-4717-8845], Gozalbo-Rovira, Roberto [0000-0003-3427-3800], Sanz-Frasquet, Carla [0000-0002-6990-3131], Bravo, Jerónimo [0000-0001-6695-2846], Rubio, Vicente [0000-0001-8124-1196], Marina, Alberto [0000-0002-1334-5273], Geller, Ron [0000-0002-7612-4611], Comas, Iñaki [0000-0001-5504-9408], Gil, Carmen [0000-0002-3882-6081], Coscollá, Mireia [0000-0003-0752-0538], Orozco, Modesto [0000-0002-8608-3278], Llácer, José Luis [0000-0001-5304-1795], Carazo, José M. [0000-0003-0788-8447], Ginex, Tiziana, Marco-Marín, Clara, Wieczor, Milosz, Mata, Carlos P., Krieger, James, López-Redondo, Marisa, Francés-Gómez, Clara, Ruiz-Rodríguez, Paula, Melero, Roberto, Sorzano, Carlos Óscar S., Martínez, Marta, Gougeard, Nadine, Forcada-Nadal, Alicia, Zamora-Caballero, Sara, Gozalbo-Rovira, Roberto, Sanz-Frasquet, Carla, Bravo, Jerónimo, Rubio, Vicente, Marina, Alberto, Geller, Ron, Comas, Iñaki, Gil, Carmen, Coscollá, Mireia, Orozco, Modesto, Llácer, José Luis, Carazo, José M., European Commission, Consejo Superior de Investigaciones Científicas (España), Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Comunidad de Madrid, European Research Council, Instituto de Salud Carlos III, Banco Santander, Generalitat Valenciana, Ginex, Tiziana [0000-0002-5739-8713], Marco-Marín, Clara [0000-0002-8813-3515], Wieczor, Milosz [0000-0003-4990-8629], Mata, Carlos P. [0000-0003-3381-7431], Krieger, James [0000-0001-6194-6244], López-Redondo, Marisa [0000-0002-3328-6821], Francés-Gómez, Clara [0000-0001-7341-3824], Ruiz-Rodríguez, Paula [0000-0003-0727-5974], Melero, Roberto [0000-0001-9467-9381], Sorzano, Carlos Óscar S. [0000-0002-9473-283X], Martínez, Marta [0000-0002-8435-5540], Gougeard, Nadine [0000-0001-7338-7267], Forcada-Nadal, Alicia [0000-0003-0179-4044], Zamora-Caballero, Sara [0000-0003-4717-8845], Gozalbo-Rovira, Roberto [0000-0003-3427-3800], Sanz-Frasquet, Carla [0000-0002-6990-3131], Bravo, Jerónimo [0000-0001-6695-2846], Rubio, Vicente [0000-0001-8124-1196], Marina, Alberto [0000-0002-1334-5273], Geller, Ron [0000-0002-7612-4611], Comas, Iñaki [0000-0001-5504-9408], Gil, Carmen [0000-0002-3882-6081], Coscollá, Mireia [0000-0003-0752-0538], Orozco, Modesto [0000-0002-8608-3278], Llácer, José Luis [0000-0001-5304-1795], Carazo, José M. [0000-0003-0788-8447], Ginex, Tiziana, Marco-Marín, Clara, Wieczor, Milosz, Mata, Carlos P., Krieger, James, López-Redondo, Marisa, Francés-Gómez, Clara, Ruiz-Rodríguez, Paula, Melero, Roberto, Sorzano, Carlos Óscar S., Martínez, Marta, Gougeard, Nadine, Forcada-Nadal, Alicia, Zamora-Caballero, Sara, Gozalbo-Rovira, Roberto, Sanz-Frasquet, Carla, Bravo, Jerónimo, Rubio, Vicente, Marina, Alberto, Geller, Ron, Comas, Iñaki, Gil, Carmen, Coscollá, Mireia, Orozco, Modesto, Llácer, José Luis, and Carazo, José M.

Abstract

The S:A222V point mutation, within the G clade, was characteristic of the 20E (EU1) SARS-CoV-2 variant identified in Spain in early summer 2020. This mutation has now reappeared in the Delta subvariant AY.4.2, raising questions about its specific effect on viral infection. We report combined serological, functional, structural and computational studies characterizing the impact of this mutation. Our results reveal that S:A222V promotes an increased RBD opening and slightly increases ACE2 binding as compared to the parent S:D614G clade. Finally, S:A222V does not reduce sera neutralization capacity, suggesting it does not affect vaccine effectiveness.

Published
2021

3. Continuous flexibility analysis of SARS-CoV-2 spike prefusion structures

Author

Consejo Superior de Investigaciones Científicas (España), Comunidad de Madrid, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Ministerio de Educación, Cultura y Deporte (España), Instituto de Salud Carlos III, European Commission, National Institutes of Health (US), Melero, Roberto [0000-0001-9467-9381], Martínez, Marta [0000-0002-8435-5540], Marabini, Roberto [0000-0001-7876-1684], Sánchez-García, Ruben [0000-0001-6156-3542], Melero, Roberto, Sorzano, Carlos Óscar S., Foster, Brent, Vilas, José Luis, Martínez, Marta, Marabini, Roberto, Ramírez-Aportela, Erney, Sánchez-García, Rubén, Herreros, David, Caño, Laura del, Losana, Patricia, Fonseca-Reyna, Yunior C., Conesa Mingo, Pablo, Wrapp, Daniel, Chacón, Pablo, McLellan, Jason S., Tagare, Hemant D., Carazo, José M., Consejo Superior de Investigaciones Científicas (España), Comunidad de Madrid, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Ministerio de Educación, Cultura y Deporte (España), Instituto de Salud Carlos III, European Commission, National Institutes of Health (US), Melero, Roberto [0000-0001-9467-9381], Martínez, Marta [0000-0002-8435-5540], Marabini, Roberto [0000-0001-7876-1684], Sánchez-García, Ruben [0000-0001-6156-3542], Melero, Roberto, Sorzano, Carlos Óscar S., Foster, Brent, Vilas, José Luis, Martínez, Marta, Marabini, Roberto, Ramírez-Aportela, Erney, Sánchez-García, Rubén, Herreros, David, Caño, Laura del, Losana, Patricia, Fonseca-Reyna, Yunior C., Conesa Mingo, Pablo, Wrapp, Daniel, Chacón, Pablo, McLellan, Jason S., Tagare, Hemant D., and Carazo, José M.

Abstract

Using a new consensus-based image-processing approach together with principal component analysis, the flexibility and conformational dynamics of the SARS-CoV-2 spike in the prefusion state have been analysed. These studies revealed concerted motions involving the receptor-binding domain (RBD), N-terminal domain, and subdomains 1 and 2 around the previously characterized 1-RBD-up state, which have been modeled as elastic deformations. It is shown that in this data set there are not well defined, stable spike conformations, but virtually a continuum of states. An ensemble map was obtained with minimum bias, from which the extremes of the change along the direction of maximal variance were modeled by flexible fitting. The results provide a warning of the potential image-processing classification instability of these complicated data sets, which has a direct impact on the interpretability of the results.

Published
2020

4. Integration of Cryo-EM Model Building Software in Scipion.

Author

Comunidad de Madrid, Marabini, Roberto [0000-0001-7876-1684], Sorzano, Carlos Oscar S. [0000-0002-9473-283X], Melero, Roberto [0000-0001-9467-9381], Cuervo, Ana [0000-0001-9414-503X], Martínez, Marta, Jiménez-Moreno, Amaya, Maluenda, David, Ramírez-Aportela, Erney, Melero, Roberto, Cuervo, Ana, Conesa Mingo, Pablo, Caño, Laura del, Fonseca-Reyna, Yunior C., Sánchez-García, Rubén, Střelák, David, Conesa, Jose J., Fernández-Giménez, Elena, Isidro, Federico de, Sorzano, Carlos Óscar S., Marabini, Roberto, Comunidad de Madrid, Marabini, Roberto [0000-0001-7876-1684], Sorzano, Carlos Oscar S. [0000-0002-9473-283X], Melero, Roberto [0000-0001-9467-9381], Cuervo, Ana [0000-0001-9414-503X], Martínez, Marta, Jiménez-Moreno, Amaya, Maluenda, David, Ramírez-Aportela, Erney, Melero, Roberto, Cuervo, Ana, Conesa Mingo, Pablo, Caño, Laura del, Fonseca-Reyna, Yunior C., Sánchez-García, Rubén, Střelák, David, Conesa, Jose J., Fernández-Giménez, Elena, Isidro, Federico de, Sorzano, Carlos Óscar S., and Marabini, Roberto

Abstract

Advances in cryo-electron microscopy (cryoEM have made possible to obtain structures of large biological macromolecules at near-atomic resolution. This "resolution-revolution'' has encouraged the use and development of modeling tools able to produce high-quality atomic models from cryoEM density maps. Unfortunately, many practical problems appear when combining different packages in the same processing workflow, which make difficult the use of these tools by non-experts and, therefore, reduce their utility. We present here a major extension of the image processing framework Scipion that provides inter-package integration in the model building area and full tracking of the complete workflow, from image processing to structure validation.

Published
2020

5. Survey of the analysis of continuous conformational variability of biological macromolecules by electron microscopy

Author

Ministerio de Economía y Competitividad (España), Comunidad de Madrid, Instituto de Salud Carlos III, National Institutes of Health (US), European Commission, Carazo, J. M [0000-0003-0788-8447], Sorzano, Carlos Óscar S. [0000-0002-9473-283X], Marabini, Roberto [0000-0001-7876-1684], Melero, Roberto [0000-0001-9467-9381], Sorzano, Carlos Óscar S., Jiménez, A., Vilas, J. L., Maluenda, D., Martínez, Marta, Ramírez-Aportela, Erney, Majtner, T., Segura, J., Sánchez-García, R., Caño, Laura del, Conesa Mingo, Pablo, Melero, Roberto, Jonic, Slavica, Vargas, Javier, Cazals, F., Freyberg, Z., Krieger, James, Bahar, Ivet, Marabini, Roberto, Carazo, José M., Ministerio de Economía y Competitividad (España), Comunidad de Madrid, Instituto de Salud Carlos III, National Institutes of Health (US), European Commission, Carazo, J. M [0000-0003-0788-8447], Sorzano, Carlos Óscar S. [0000-0002-9473-283X], Marabini, Roberto [0000-0001-7876-1684], Melero, Roberto [0000-0001-9467-9381], Sorzano, Carlos Óscar S., Jiménez, A., Vilas, J. L., Maluenda, D., Martínez, Marta, Ramírez-Aportela, Erney, Majtner, T., Segura, J., Sánchez-García, R., Caño, Laura del, Conesa Mingo, Pablo, Melero, Roberto, Jonic, Slavica, Vargas, Javier, Cazals, F., Freyberg, Z., Krieger, James, Bahar, Ivet, Marabini, Roberto, and Carazo, José M.

Abstract

Single-particle analysis by electron microscopy is a well established technique for analyzing the three-dimensional structures of biological macromolecules. Besides its ability to produce high-resolution structures, it also provides insights into the dynamic behavior of the structures by elucidating their conformational variability. Here, the different image-processing methods currently available to study continuous conformational changes are reviewed.

Published
2019

6. Ribosome-associated vesicles: A dynamic subcompartment of the endoplasmic reticulum in secretory cells

Author

Stephen D. Carter, Wen Li, Sandra A. Murray, Deborah Fass, Jenny I. Aguilar, José María Carazo, Meir Aridor, Michael J. Calderon, Sruti Shiva, Leanna Eisenman, Zachary J. Farino, Elana S. Levy, Stephanie E. Siegmund, William J. Rice, Allen Volchuk, Jyotsna Pilli, Edward Yi, Robin Freyberg, Robert A. Grassucci, Christoph Wigge, Tamas Balla, Grant J. Jensen, Zachary Freyberg, Nili L. Greenberg, Roberto Melero, Kenneth N. Fish, Travis J Morgenstern, Cheri M. Hampton, Estela Area-Gomez, Maïté Courel, Joshua G. Pemberton, Sharon G. Wolf, Callen T. Wallace, William G. Mitchell, Joachim Frank, Emily W. George, Simon C. Watkins, Ngoc-Han Tran, Zachary P. Wills, Robert Langlois, Despoina Aslanoglou, Francesca Bartolini, Peter Walter, Jonathan A. Javitch, European Research Council, Ministerio de Economía y Competitividad (España), Comunidad de Madrid, Melero, Roberto, Carazo, José María, Melero, Roberto [0000-0001-9467-9381], and Carazo, José María [0000-0003-0788-8447]

Subjects
Cell type, Physiological, Cell, Golgi Apparatus, Mitochondrion, Endoplasmic Reticulum, Stress, Ribosome, 03 medical and health sciences, Mice, 0302 clinical medicine, Rare Diseases, Stress, Physiological, medicine, Animals, Research Articles, 030304 developmental biology, 0303 health sciences, Multidisciplinary, Chemistry, Vesicle, Endoplasmic reticulum, Cytoplasmic Vesicles, Cryoelectron Microscopy, SciAdv r-articles, Biological Transport, Cell Biology, 3. Good health, Cell biology, Mitochondria, Rats, Molecular Imaging, Membrane, medicine.anatomical_structure, Organ Specificity, Reticular connective tissue, Generic health relevance, Ribosomes, 030217 neurology & neurosurgery, Research Article
Abstract

The endoplasmic reticulum (ER) is a highly dynamic network of membranes. Here, we combine live-cell microscopy with in situ cryo-electron tomography to directly visualize ER dynamics in several secretory cell types including pancreatic β-cells and neurons under near-native conditions. Using these imaging approaches, we identify a novel, mobile form of ER, ribosome-associated vesicles (RAVs), found primarily in the cell periphery, which is conserved across different cell types and species. We show that RAVs exist as distinct, highly dynamic structures separate from the intact ER reticular architecture that interact with mitochondria via direct intermembrane contacts. These findings describe a new ER subcompartment within cells., Support for this study was provided by the L. V. Gerstner Jr., Scholars Program (to Z.F.), the Leon Levy Foundation (to Z.F.), the John F. and Nancy A. Emmerling Fund of the Pittsburgh Foundation (to Z.F.), the Department of Defense PR141292 (to Z.F.), NIH K08DA031241 (to Z.F.), NSF MCB-1408986 (to S.A.M.), the National Science Foundation Graduate Research Fellowship (to N.H.T.), NIH K01AG045335 (to E.A.G.), NIH 1S10RR019003 (to S.C.W.), NIH 1S10RR025488 (to S.C.W.), NIH 1S10RR016236 (to S.C.W.), NIH F30NS093798 (to S.E.S.), NIH R56AG058593 (to Z.P.W.), the Howard Hughes Medical Institute (to P.W., N.H.T., J.F., and G.J.J.), NIH GM29169 (to J.F.), NIH GM122588 (to G.J.J.), NIH AI150464 (to G.J.J.), the Israel Science Foundation Grant 1285/14 (to S.G.W.), the European Research Council under the European Union’s Seventh Framework Programme (grant number 310649) (to D.F.), MINECO AIC-A-2011-0638 (to J.M.C.), the Spanish Ministry of Economy and Competitiveness grant BIO2016-76400-R AEI/FEDER, UE (to J.M.C.), and Comunidad Autónoma de Madrid grant S2017/BMD-3817 (to J.M.C.). Some of the cryo-ET was performed in the Beckman Institute Resource Center for Transmission EM at Caltech. Additional work was also performed at the Simons Electron Microscopy Center and National Resource for Automated Molecular Microscopy located at the New York Structural Biology Center, supported by grants from the Simons Foundation (349247), NYSTAR, and the NIH National Institute of General Medical Sciences (GM103310) with added support from NIH S10 RR029300-01. CSTET data acquisition was partially supported by the Irving and Cherna Moskowitz Center for Nano and Bio-Nano Imaging at the Weizmann Institute of Science. Some of the live confocal images were collected and processed in the Confocal and Specialized Microscopy Shared Resource of the Herbert Irving Comprehensive Cancer Center at Columbia University and supported by NIH P30 CA013696. Part of the cryo-EM image processing was conducted as an Instruct-ERIC collaboration project PD1222 at the Instruct Image Processing Center

Published
2020

7. Continuous flexibility analysis of SARS-CoV-2 spike prefusion structures

Author

Pablo Chacón, Laura del Cano, José María Carazo, Pablo Conesa, Roberto Marabini, Erney Ramírez-Aportela, C.O.S. Sorzano, Hemant D. Tagare, Jason S. McLellan, Daniel Wrapp, Patricia Losana, Rubén J. Sánchez-García, Brent Foster, José Luis Vilas, David Herreros, Roberto Melero, Yunior C. Fonseca-Reyna, Marta Martínez, Consejo Superior de Investigaciones Científicas (España), Comunidad de Madrid, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Ministerio de Educación, Cultura y Deporte (España), Instituto de Salud Carlos III, European Commission, National Institutes of Health (US), Melero, Roberto [0000-0001-9467-9381], Martínez, Marta [0000-0002-8435-5540], Marabini, Roberto [0000-0001-7876-1684], Sánchez-García, Ruben [0000-0001-6156-3542], Melero, Roberto, Martínez, Marta, Marabini, Roberto, Sánchez-García, Ruben, and UAM. Departamento de Ingeniería Informática

Subjects
conformational flexibility, Computer science, Image processing, Spike, cryo-electron microscopy, Instability, Biochemistry, Conformational flexibility, Domain (mathematical analysis), Article, Domain (software engineering), 03 medical and health sciences, 0302 clinical medicine, General Materials Science, Statistical physics, Cluster analysis, 030304 developmental biology, Interpretability, Informática, Physics, Flexibility (engineering), 0303 health sciences, Crystallography, SARS-CoV-2, State (functional analysis), General Chemistry, spike, Condensed Matter Physics, Research Papers, Cryo-electron microscopy (cryo-EM), image processing, Data set, sars-cov-2, QD901-999, Principal component analysis, Spike (software development), Algorithm, 030217 neurology & neurosurgery
Abstract

Using a new consensus-based image-processing approach together with principal component analysis, the flexibility and conformational dynamics of the SARS-CoV-2 spike in the prefusion state have been analysed. These studies revealed concerted motions involving the receptor-binding domain (RBD), N-terminal domain, and subdomains 1 and 2 around the previously characterized 1-RBD-up state, which have been modeled as elastic deformations. It is shown that in this data set there are not well defined, stable spike conformations, but virtually a continuum of states. An ensemble map was obtained with minimum bias, from which the extremes of the change along the direction of maximal variance were modeled by flexible fitting. The results provide a warning of the potential image-processing classification instability of these complicated data sets, which has a direct impact on the interpretability of the results., The authors would like to acknowledge financial support from CSIC (PIE/COVID-19 No. 202020E079), the Comunidad de Madrid through grant CAM (S2017/BMD-3817), the Spanish Ministry of Science and Innovation through projects SEV 2017-0712, FPU-2015/264 and PID2019-104757RB-I00/AEI/FEDER, the Instituto de Salud Carlos III [PT17/0009/0010 (ISCIII-SGEFI/ERDF)], and the European Union and Horizon 2020 through grants INSTRUCT–ULTRA (INFRADEV-03-2016-2017, Proposal 731005), EOSC Life (INFRAEOSC-04-2018, Proposal 824087), HighResCells (ERC-2018-SyG, Proposal 810057), IMpaCT (WIDESPREAD-03-2018, Proposal 857203), CORBEL (INFRADEV-1-2014-1, Proposal 654248) and EOSC–Synergy (EINFRA-EOSC-5, Proposal 857647). HDT and BF were supported by NIH grant GM125769 and JSM was supported by NIH grant R01-AI127521.

Published
2020
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8. Survey of the analysis of continuous conformational variability of biological macromolecules by electron microscopy

Author

Zachary Freyberg, Roberto Marabini, Carlos Oscar S. Sorzano, F Cazals, A. Jimenez, David Maluenda, Y. Rancel, Rubén J. Sánchez-García, María Jesús Martínez, L. del Cano, Javier Mota, Roberto Melero, José María Carazo, José Luis Vilas, Pablo Conesa, Joan Segura, Slavica Jonic, Javier Vargas, Ivet Bahar, James Krieger, Tomáš Majtner, Erney Ramírez-Aportela, Centro Nacional de Biotecnología [Madrid] (CNB-CSIC), Biocomputing Unit [Madrid], Institut de minéralogie, de physique des matériaux et de cosmochimie (IMPMC), Muséum national d'Histoire naturelle (MNHN)-Institut de recherche pour le développement [IRD] : UR206-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), McGill University = Université McGill [Montréal, Canada], Algorithms, Biology, Structure (ABS), Inria Sophia Antipolis - Méditerranée (CRISAM), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE), Universidad Autonoma de Madrid (UAM), ANR-19-P3IA-0002,3IA@cote d'azur,3IA Côte d'Azur(2019), UAM. Departamento de Ingeniería Informática, Tratamiento de Señales Biomédicas (ING EPS-011), Ministerio de Economía y Competitividad (España), Comunidad de Madrid, Instituto de Salud Carlos III, National Institutes of Health (US), European Commission, Carazo, J. M, Sorzano, Carlos Óscar S., Marabini, Roberto, Melero, Roberto, Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), Universidad Autónoma de Madrid (UAM), Carazo, J. M [0000-0003-0788-8447], Sorzano, Carlos Óscar S. [0000-0002-9473-283X], Marabini, Roberto [0000-0001-7876-1684], and Melero, Roberto [0000-0001-9467-9381]

Subjects
Materials science, Macromolecular Substances, Molecular Conformation, Biophysics, Single particle analysis, Electrons, Molecular Dynamics Simulation, [INFO.INFO-CG]Computer Science [cs]/Computational Geometry [cs.CG], Biochemistry, law.invention, 03 medical and health sciences, Imaging, Three-Dimensional, Image processing, Structural Biology, Normal mode, law, Continuous heterogeneity, Image Processing, Computer-Assisted, Genetics, Electron microscopy, Humans, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Informática, Principal Component Analysis, 0303 health sciences, 030302 biochemistry & molecular biology, Proteins, Single-particle analysis, Condensed Matter Physics, 3. Good health, Microscopy, Electron, Thermodynamics, Normal-mode analysis, Electron microscope, Cryo-Electron Microscopy, Algorithms, Macromolecule
Abstract

Single-particle analysis by electron microscopy is a well established technique for analyzing the three-dimensional structures of biological macromolecules. Besides its ability to produce high-resolution structures, it also provides insights into the dynamic behavior of the structures by elucidating their conformational variability. Here, the different image-processing methods currently available to study continuous conformational changes are reviewed., Spanish Ministry of Economy and Competitiveness through grants BIO2013-44647-R and BIO2016-76400-R (AEI/FEDER, UE), Comunidad Autonoma de Madrid through grant S2017/BMD-3817, Instituto de Salud Carlos III through grants PT13/0001/0009 and PT17/0009/0010, the European Union (EU) and Horizon 2020 through West-Life (EINFRA-2015-1, Proposal 675858), CORBEL (INFRADEV-1-2014-1, Proposal 654248), ELIXIR–EXCELERATE (INFRADEV-3-2015, Proposal 676559), iNEXT (INFRAIA-1-2014-2015, Proposal 653706), EOSCpilot (INFRADEV-04-2016, Proposal 739563) and the National Institutes of Health (P41GM 103712) (IB).

Published
2019

9. The structural role of SARS-CoV-2 genetic background in the emergence and success of spike mutations: the case of the spike A222V mutation

Author

Ginex, Tiziana, Marco-Marín, Clara, Wieczór, Miłosz, Mata, Carlos P., Krieger, James, López-Redondo, Maria Luisa, Francés-Gómez, Clara, Ruiz-Rodriguez, Paula, Melero, Roberto, Sánchez-Sorzano, Carlos Óscar, Martínez, Marta, Gougeard, Nadine, Forcada-Nadal, Alicia, Zamora-Caballero, Sara, Gozalbo-Rovira, Roberto, Sanz-Frasquet, Carla, Bravo, Jeronimo, Rubio, Vicente, Marina, Alberto, Geller, Ron, Comas, Iñaki, Gil, Carmen, Coscolla, Mireia, Orozco, Modesto, Llácer, José Luis, Carazo, José-Maria, European Commission, Consejo Superior de Investigaciones Científicas (España), Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Comunidad de Madrid, European Research Council, Instituto de Salud Carlos III, Banco Santander, Generalitat Valenciana, Ginex, Tiziana [0000-0002-5739-8713], Marco-Marín, Clara [0000-0002-8813-3515], Wieczor, Milosz [0000-0003-4990-8629], Mata, Carlos P. [0000-0003-3381-7431], Krieger, James [0000-0001-6194-6244], López-Redondo, Marisa [0000-0002-3328-6821], Francés-Gómez, Clara [0000-0001-7341-3824], Ruiz-Rodríguez, Paula [0000-0003-0727-5974], Melero, Roberto [0000-0001-9467-9381], Sorzano, Carlos Óscar S. [0000-0002-9473-283X], Martínez, Marta [0000-0002-8435-5540], Gougeard, Nadine [0000-0001-7338-7267], Forcada-Nadal, Alicia [0000-0003-0179-4044], Zamora-Caballero, Sara [0000-0003-4717-8845], Gozalbo-Rovira, Roberto [0000-0003-3427-3800], Sanz-Frasquet, Carla [0000-0002-6990-3131], Bravo, Jerónimo [0000-0001-6695-2846], Rubio, Vicente [0000-0001-8124-1196], Marina, Alberto [0000-0002-1334-5273], Geller, Ron [0000-0002-7612-4611], Comas, Iñaki [0000-0001-5504-9408], Gil, Carmen [0000-0002-3882-6081], Coscollá, Mireia [0000-0003-0752-0538], Orozco, Modesto [0000-0002-8608-3278], Llácer, José Luis [0000-0001-5304-1795], Carazo, José M. [0000-0003-0788-8447], Ginex, Tiziana, Marco-Marín, Clara, Wieczor, Milosz, Mata, Carlos P., Krieger, James, López-Redondo, Marisa, Francés-Gómez, Clara, Ruiz-Rodríguez, Paula, Melero, Roberto, Sorzano, Carlos Óscar S., Martínez, Marta, Gougeard, Nadine, Forcada-Nadal, Alicia, Zamora-Caballero, Sara, Gozalbo-Rovira, Roberto, Sanz-Frasquet, Carla, Bravo, Jerónimo, Rubio, Vicente, Marina, Alberto, Geller, Ron, Comas, Iñaki, Gil, Carmen, Coscollá, Mireia, Orozco, Modesto, Llácer, José Luis, and Carazo, José M.

Subjects
0303 health sciences, 03 medical and health sciences, 010402 general chemistry, 01 natural sciences, 3. Good health, 030304 developmental biology, 0104 chemical sciences
Abstract

The S:A222V point mutation, within the G clade, was characteristic of the 20E (EU1) SARS-CoV-2 variant identified in Spain in early summer 2020. This mutation has now reappeared in the Delta subvariant AY.4.2, raising questions about its specific effect on viral infection. We report combined serological, functional, structural and computational studies characterizing the impact of this mutation. Our results reveal that S:A222V promotes an increased RBD opening and slightly increases ACE2 binding as compared to the parent S:D614G clade. Finally, S:A222V does not reduce sera neutralization capacity, suggesting it does not affect vaccine effectiveness., This research work was supported by the European Commission–NextGenerationEU through the CSIC Global Health Platform. Additionally, authors would like to acknowledge economic support from the Spanish Ministry of Science and Innovation through Grants: PID2019-104757RB-I00 funded by MCIN/AEI/ 10.13039/501100011033, RTI2018-094399-A-I00, and “ERDF A way of making Europe”, by the “European Union”, Grant SEV 2017-0712 funded by MCIN/AEI /10.13039/501100011033, the “Comunidad Autónoma de Madrid" through Grant: S2017/BMD3817, and the European Union (EU) and Horizon 2020 through grants: Marie-Curie Fellowship EnLaCES (MSCA IF 2020, Proposal: 101024130) (to JK), HighResCells (ERC - 2018 - SyG, Proposal: 810057), and iNEXT-Discovery (Proposal: 871037). AM, VR, JB and JLL are funded by CIBERER-ISCIII (proposal: COV20/00437), Fondo Supera COVID-19 (proposal: CSICCOVID19-082), Banco Santander (Proposal: BlockAce), and CSIC PTI Salud Global (Proposal: 202080E110). VR is funded by the Spanish Ministry of Science and Innovation through Grant PID2020-120322RB-C21. IC is funded by project PID2019-104477RB-100, Fondo COVID COV20/00140 and ERC CoG 101001038. MC is funded by the RyC program from the Spanish Ministry of Science and Innovation, the Generalitat Valenciana (SEJI/2019/011).

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10. The structural role of SARS-CoV-2 genetic background in the emergence and success of spike mutations: The case of the spike A222V mutation

Author

Ginex, Tiziana, Marco-Marín, Clara, Wieczor, Milosz, Mata, Carlos P., Krieger, James, Ruiz-Rodríguez, Paula, López-Redondo, Marisa, Francés-Gómez, Clara, Melero, Roberto, Sorzano, Carlos Óscar S., Martínez, Marta, Gougeard, Nadine, Forcada-Nadal, Alicia, Zamora-Caballero, Sara, Gozalbo-Rovira, Roberto, Sanz-Frasquet, Carla, Arranz, Rocío, Bravo, Jerónimo, Rubio, Vicente, Marina, Alberto, The IBV-Covid19-Pipeline, Geller, Ron, Comas, Iñaki, Gil, Carmen, Coscollá, Mireia, Orozco, Modesto, Llácer, José Luis, Carazo, José M., European Commission, Consejo Superior de Investigaciones Científicas (España), Ministerio de Ciencia e Innovación (España), Generalitat Valenciana, Comunidad de Madrid, Banco Santander, Instituto de Salud Carlos III, Ginex, Tiziana [0000-0002-5739-8713], Marco-Marín, Clara [0000-0002-8813-3515], Wieczor, Milosz [0000-0003-4990-8629], Mata, Carlos P. [0000-0003-3381-7431], Krieger, James [0000-0001-6194-6244], Ruiz-Rodríguez, Paula [0000-0003-0727-5974], López-Redondo, Marisa [0000-0002-3328-6821], Francés-Gómez, Clara [0000-0001-7341-3824], Melero, Roberto [0000-0001-9467-9381], Sorzano, Carlos Óscar S. [0000-0002-9473-283X], Martínez, Marta [0000-0002-8435-5540], Gougeard, Nadine [0000-0001-7338-7267], Forcada-Nadal, Alicia [0000-0003-0179-4044], Zamora-Caballero, Sara [0000-0003-4717-8845], Gozalbo-Rovira, Roberto [0000-0003-3427-3800], Sanz-Frasquet, Carla [0000-0002-6990-3131], Arranz, Rocío [0000-0001-5321-0915], Bravo, Jerónimo [0000-0001-6695-2846], Rubio, Vicente [0000-0001-8124-1196], Marina, Alberto [0000-0002-1334-5273], Geller, Ron [0000-0002-7612-4611], Comas, Iñaki [0000-0001-5504-9408], Gil, Carmen [0000-0002-3882-6081], Coscollá, Mireia [0000-0003-0752-0538], Orozco, Modesto [0000-0002-8608-3278], Llácer, José Luis [0000-0001-5304-1795], Carazo, José M. [0000-0003-0788-8447], Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Ministerio de Economía y Competitividad (España), Ginex, Tiziana, Marco-Marín, Clara, Wieczor, Milosz, Mata, Carlos P., Krieger, James, Ruiz-Rodríguez, Paula, López-Redondo, Marisa, Francés-Gómez, Clara, Melero, Roberto, Sorzano, Carlos Óscar S., Martínez, Marta, Gougeard, Nadine, Forcada-Nadal, Alicia, Zamora-Caballero, Sara, Gozalbo-Rovira, Roberto, Sanz-Frasquet, Carla, Arranz, Rocío, Bravo, Jerónimo, Rubio, Vicente, Marina, Alberto, Geller, Ron, Comas, Iñaki, Gil, Carmen, Coscollá, Mireia, Orozco, Modesto, Llácer, José Luis, and Carazo, José M.

Subjects
Vaccines, SARS-CoV-2, Mutació (Biologia), Immunology, COVID-19, Peptidyl-Dipeptidase A, Mutation (Biology), Vacunes, Infections, Microbiology, Infeccions, Virology, Mutation, Spike Glycoprotein, Coronavirus, Genetics, Humans, Receptors, Virus, Parasitology, Angiotensin-Converting Enzyme 2, Genetic Background, Molecular Biology, Protein Binding
Abstract

The S:A222V point mutation, within the G clade, was characteristic of the 20E (EU1) SARS-CoV-2 variant identified in Spain in early summer 2020. This mutation has since reappeared in the Delta subvariant AY.4.2, raising questions about its specific effect on viral infection. We report combined serological, functional, structural and computational studies characterizing the impact of this mutation. Our results reveal that S:A222V promotes an increased RBD opening and slightly increases ACE2 binding as compared to the parent S:D614G clade. Finally, S:A222V does not reduce sera neutralization capacity, suggesting it does not affect vaccine effectiveness., In this research work, PRR and TG were supported by salaries from the European Commission–NextGenerationEU through the CSIC Global Health Platform established by EU Council Regulation 2020/2094. The authors would like to acknowledge economic support from: (a) the Spanish Ministry of Science and Innovation through grants: SEV-2017-0712 funded by MCIN/AEI/10.13039/501100011033 (CPM, JK, RM, COSS, MM, RA, JMC); 116880GB-I00 (JLL) and 120322RB-C21 (VR) funded within PID 2020; PID2019-104757RB-I00 funded by MCIN/AEI/10.13039/501100011033/ and “ERDF A way of making Europe”, by the “European Union” (JMC, COSS, RM, MM, CPM) and 104477RB-100 (IC) funded within PID 2019; RYC-2015-18213 (salary of MC) and RYC-2015-17517 (salary of RG) funded by the Ramon y Cajal fellowship program; RTI2018-094399-A-I00 (JMC, COSS, RM, CPM, MC) funded within the Retos Investigación program; the CRIOMECORR project funded as ESFRI-2019-01-CSIC-16; (b) the Horizon 2020 program through Marie Skłodowska-Curie Individual Fellowships EnLaCES (Proposal 101024130, salary of JK) and EPIDNA (Grant ID: 894498, salary of MW); (c) the European Research Council (ERC) through grants: ERC-2018-SyG-810057 HighResCells funded within the EXCELLENT SCIENCE program (JMC, MM, COSS, salary of RM), Grant 871037 iNEXT DISCOVERY (JMC, MM, COSS) and grant CoG-101001038 funded within the Consolidator Grants program (IC); (d) Generalitat Valenciana through grants: SEJI/2019/011 (MC) and SEJI/2019/030 (JLL); (e) Comunidad de Madrid through grant: S2017/BMD-3817 (JMC); (f) Santander Bank through grant: CSIC-COVID19-082 (AM, VR, JB, JLL, RG) funded through the Fondo Supera Covid-19; (g) Instituto de Salud Carlos III through grants: COV20/00437 (AM, VR, JB, JLL) and COV20/00140 (IC), both funded through the Fondos Covid-19 initiative; (h) Spanish National Research Council through grant: 202080E110 funded within the PTI Salud Global initiative (AM, VR, JB, JLL, RG).

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