Multiscale molecular simulations to investigate adenylyl cyclase-based signaling in the brain
20 pages, 9 figures, 1 box, supporting information https://doi.org/10.1002/wcms.1623.-- Data availabitity statement: Data sharing is not applicable to this article as no new data were created or analyzed in this study.
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| Format: | artículo biblioteca |
| Language: | English |
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John Wiley & Sons
2023-01
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| Subjects: | Adenylyl cyclases, Molecular simulation, Systems biology modeling, |
| Online Access: | http://hdl.handle.net/10261/289518 |
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dig-icm-es-10261-2895182023-02-16T14:53:53Z Multiscale molecular simulations to investigate adenylyl cyclase-based signaling in the brain Keulen, Siri van Martin, Juliette Colizzi, Francesco Frezza, Elisa Trpevski, Daniel Cirauqui Diaz, Nuria Vidossich, Pietro Rothlisberger, Ursula Hellgren Kotaleski, Jeanette Wade, Rebecca C. Carloni, Paolo European Commission Swedish Research Council Agencia Estatal de Investigación (España) Adenylyl cyclases Molecular simulation Systems biology modeling 20 pages, 9 figures, 1 box, supporting information https://doi.org/10.1002/wcms.1623.-- Data availabitity statement: Data sharing is not applicable to this article as no new data were created or analyzed in this study. Adenylyl cyclases (ACs) play a key role in many signaling cascades. ACs catalyze the production of cyclic AMP from ATP and this function is stimulated or inhibited by the binding of their cognate stimulatory or inhibitory Gα subunits, respectively. Here we used simulation tools to uncover the molecular and subcellular mechanisms of AC function, with a focus on the AC5 isoform, extensively studied experimentally. First, quantum mechanical/molecular mechanical free energy simulations were used to investigate the enzymatic reaction and its changes upon point mutations. Next, molecular dynamics simulations were employed to assess the catalytic state in the presence or absence of Gα subunits. This led to the identification of an inactive state of the enzyme that is present whenever an inhibitory Gα is associated, independent of the presence of a stimulatory Gα. In addition, the use of coevolution-guided multiscale simulations revealed that the binding of Gα subunits reshapes the free-energy landscape of the AC5 enzyme by following the classical population-shift paradigm. Finally, Brownian dynamics simulations provided forward rate constants for the binding of Gα subunits to AC5, consistent with the ability of the protein to perform coincidence detection effectively. Our calculations also pointed to strong similarities between AC5 and other AC isoforms, including AC1 and AC6. Findings from the molecular simulations were used along with experimental data as constraints for systems biology modeling of a specific AC5-triggered neuronal cascade to investigate how the dynamics of downstream signaling depend on initial receptor activation Jeanette Hellgren Kotaleski, Paolo Carloni, Rebecca C. Wade: Horizon 2020 Framework Programme (945539, HBP SGA3); Jeanette Hellgren Kotaleski: Swedish Research Council (VR-M-2017-02806, VR-M-2020-01652); Swedish e-science Research Center (SeRC). Francesco Colizzi is a Ramón y Cajal Fellow (RYC2019-026768-I). Rebecca C. Wade: Klaus Tschira Foundation. [...] The ICM-CSIC is recipient of the Severo Ochoa Centre of Excellence accreditation (CEX2019-000928-S) from the Spanish Ministry of Science and Innovation. Peer reviewed 2023-02-16T10:25:31Z 2023-02-16T10:25:31Z 2023-01 artículo WIREs: Computational Molecular Science 13(1): e1623 (2023) CEX2019-000928-S http://hdl.handle.net/10261/289518 10.1002/wcms.1623 1759-0884 en #PLACEHOLDER_PARENT_METADATA_VALUE# info:eu-repo/grantAgreement/EC/H2020/945539 Publisher's version https://doi.org/10.1002/wcms.1623 Sí open John Wiley & Sons |
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Adenylyl cyclases Molecular simulation Systems biology modeling Adenylyl cyclases Molecular simulation Systems biology modeling |
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Adenylyl cyclases Molecular simulation Systems biology modeling Adenylyl cyclases Molecular simulation Systems biology modeling Keulen, Siri van Martin, Juliette Colizzi, Francesco Frezza, Elisa Trpevski, Daniel Cirauqui Diaz, Nuria Vidossich, Pietro Rothlisberger, Ursula Hellgren Kotaleski, Jeanette Wade, Rebecca C. Carloni, Paolo Multiscale molecular simulations to investigate adenylyl cyclase-based signaling in the brain |
| description |
20 pages, 9 figures, 1 box, supporting information https://doi.org/10.1002/wcms.1623.-- Data availabitity statement: Data sharing is not applicable to this article as no new data were created or analyzed in this study. |
| author2 |
European Commission |
| author_facet |
European Commission Keulen, Siri van Martin, Juliette Colizzi, Francesco Frezza, Elisa Trpevski, Daniel Cirauqui Diaz, Nuria Vidossich, Pietro Rothlisberger, Ursula Hellgren Kotaleski, Jeanette Wade, Rebecca C. Carloni, Paolo |
| format |
artículo |
| topic_facet |
Adenylyl cyclases Molecular simulation Systems biology modeling |
| author |
Keulen, Siri van Martin, Juliette Colizzi, Francesco Frezza, Elisa Trpevski, Daniel Cirauqui Diaz, Nuria Vidossich, Pietro Rothlisberger, Ursula Hellgren Kotaleski, Jeanette Wade, Rebecca C. Carloni, Paolo |
| author_sort |
Keulen, Siri van |
| title |
Multiscale molecular simulations to investigate adenylyl cyclase-based signaling in the brain |
| title_short |
Multiscale molecular simulations to investigate adenylyl cyclase-based signaling in the brain |
| title_full |
Multiscale molecular simulations to investigate adenylyl cyclase-based signaling in the brain |
| title_fullStr |
Multiscale molecular simulations to investigate adenylyl cyclase-based signaling in the brain |
| title_full_unstemmed |
Multiscale molecular simulations to investigate adenylyl cyclase-based signaling in the brain |
| title_sort |
multiscale molecular simulations to investigate adenylyl cyclase-based signaling in the brain |
| publisher |
John Wiley & Sons |
| publishDate |
2023-01 |
| url |
http://hdl.handle.net/10261/289518 |
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