The Dynamical Asymmetry in SARS-CoV2 Protease Reveals the Exchange Between Catalytic Activity and Stability in Homodimers
The molecular approach to understanding the mechanisms of emerging diseases, like COVID-19, has largely accelerated the search for successful therapeutical strategies. In this work, we present an extensive molecular dynamics (MD) analysis of two forms of the SARS-CoV-2 main protease M<sup>Pro&...
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MDPI AG
2025-03-01
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| author | Velia Minicozzi Alessandro Giuliani Giampiero Mei Leonardo Domenichelli Mauro Parise Almerinda Di Venere Luisa Di Paola |
| author_facet | Velia Minicozzi Alessandro Giuliani Giampiero Mei Leonardo Domenichelli Mauro Parise Almerinda Di Venere Luisa Di Paola |
| author_sort | Velia Minicozzi |
| collection | DOAJ |
| description | The molecular approach to understanding the mechanisms of emerging diseases, like COVID-19, has largely accelerated the search for successful therapeutical strategies. In this work, we present an extensive molecular dynamics (MD) analysis of two forms of the SARS-CoV-2 main protease M<sup>Pro</sup>. We analyzed the free form (apo) and compared the results with those coming from the (holo) form bound to the inhibitor Boceprevir, an FDA-approved drug repurposed for COVID-19 therapy. We applied Dynamic Cross Correlation (DCC) analysis to the MD simulations to trace the concerted motion patterns within the protein structure. Although symmetric, the homodimer in the bound form showed clearly asymmetric dynamical behavior. In particular, the presence of concerted motions was detected in the protomer where the expulsion of the substrate from the active site happened. Such behavior was not observed in the same time lapses in the apo form. These results highlight a sort of ‘symmetry breaking’, making a symmetric structure to display functional induced asymmetric behavior in response to a perturbation. This highly coordinated dynamics in response to an external cue confirms the character of ‘complex molecular machines’ of biopolymers. |
| format | Article |
| id | doaj-art-988bbbb3a0de48b99151dff273a94423 |
| institution | DOAJ |
| issn | 1420-3049 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj-art-988bbbb3a0de48b99151dff273a944232025-08-20T03:08:57ZengMDPI AGMolecules1420-30492025-03-01307141210.3390/molecules30071412The Dynamical Asymmetry in SARS-CoV2 Protease Reveals the Exchange Between Catalytic Activity and Stability in HomodimersVelia Minicozzi0Alessandro Giuliani1Giampiero Mei2Leonardo Domenichelli3Mauro Parise4Almerinda Di Venere5Luisa Di Paola6INFN and Department of Physics, University of Rome Tor Vergata, 00133 Rome, ItalyDepartment of Environment and Health, Istituto Superiore di Sanità, 00161 Rome, ItalyDepartment of Experimental Medicine, University of Rome Tor Vergata, 00133 Rome, ItalyUnit of Chemical-Physics Fundamentals in Chemical Engineering, Department of Science and Technology for Sustainable Development and One Health, Università Campus Bio-Medico of Rome, 00128 Rome, ItalyUnit of Electrotechnics, Department of Engineering, Università Campus Bio-Medico of Rome, 00128 Rome, ItalyDepartment of Experimental Medicine, University of Rome Tor Vergata, 00133 Rome, ItalyUnit of Chemical-Physics Fundamentals in Chemical Engineering, Department of Science and Technology for Sustainable Development and One Health, Università Campus Bio-Medico of Rome, 00128 Rome, ItalyThe molecular approach to understanding the mechanisms of emerging diseases, like COVID-19, has largely accelerated the search for successful therapeutical strategies. In this work, we present an extensive molecular dynamics (MD) analysis of two forms of the SARS-CoV-2 main protease M<sup>Pro</sup>. We analyzed the free form (apo) and compared the results with those coming from the (holo) form bound to the inhibitor Boceprevir, an FDA-approved drug repurposed for COVID-19 therapy. We applied Dynamic Cross Correlation (DCC) analysis to the MD simulations to trace the concerted motion patterns within the protein structure. Although symmetric, the homodimer in the bound form showed clearly asymmetric dynamical behavior. In particular, the presence of concerted motions was detected in the protomer where the expulsion of the substrate from the active site happened. Such behavior was not observed in the same time lapses in the apo form. These results highlight a sort of ‘symmetry breaking’, making a symmetric structure to display functional induced asymmetric behavior in response to a perturbation. This highly coordinated dynamics in response to an external cue confirms the character of ‘complex molecular machines’ of biopolymers.https://www.mdpi.com/1420-3049/30/7/1412molecular dynamics (MD) simulationmain protease (M<sup>Pro</sup>)SARS-CoV-2structural analysisdrug discoverytherapeutic interventions |
| spellingShingle | Velia Minicozzi Alessandro Giuliani Giampiero Mei Leonardo Domenichelli Mauro Parise Almerinda Di Venere Luisa Di Paola The Dynamical Asymmetry in SARS-CoV2 Protease Reveals the Exchange Between Catalytic Activity and Stability in Homodimers Molecules molecular dynamics (MD) simulation main protease (M<sup>Pro</sup>) SARS-CoV-2 structural analysis drug discovery therapeutic interventions |
| title | The Dynamical Asymmetry in SARS-CoV2 Protease Reveals the Exchange Between Catalytic Activity and Stability in Homodimers |
| title_full | The Dynamical Asymmetry in SARS-CoV2 Protease Reveals the Exchange Between Catalytic Activity and Stability in Homodimers |
| title_fullStr | The Dynamical Asymmetry in SARS-CoV2 Protease Reveals the Exchange Between Catalytic Activity and Stability in Homodimers |
| title_full_unstemmed | The Dynamical Asymmetry in SARS-CoV2 Protease Reveals the Exchange Between Catalytic Activity and Stability in Homodimers |
| title_short | The Dynamical Asymmetry in SARS-CoV2 Protease Reveals the Exchange Between Catalytic Activity and Stability in Homodimers |
| title_sort | dynamical asymmetry in sars cov2 protease reveals the exchange between catalytic activity and stability in homodimers |
| topic | molecular dynamics (MD) simulation main protease (M<sup>Pro</sup>) SARS-CoV-2 structural analysis drug discovery therapeutic interventions |
| url | https://www.mdpi.com/1420-3049/30/7/1412 |
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