Energy landscape of the SARS-CoV-2 reveals extensive conformational heterogeneity
Cryo-electron microscopy (cryo-EM) has produced a number of structural models of the SARS-CoV-2 spike, already prompting biomedical outcomes. However, these reported models and their associated electrostatic potential maps represent an unknown admixture of conformations stemming from the underlying...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2022-01-01
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| Series: | Current Research in Structural Biology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2665928X22000034 |
| _version_ | 1828265780911800320 |
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| author | Ghoncheh Mashayekhi John Vant Abhigna Polavarapu Abbas Ourmazd Abhishek Singharoy |
| author_facet | Ghoncheh Mashayekhi John Vant Abhigna Polavarapu Abbas Ourmazd Abhishek Singharoy |
| author_sort | Ghoncheh Mashayekhi |
| collection | DOAJ |
| description | Cryo-electron microscopy (cryo-EM) has produced a number of structural models of the SARS-CoV-2 spike, already prompting biomedical outcomes. However, these reported models and their associated electrostatic potential maps represent an unknown admixture of conformations stemming from the underlying energy landscape of the spike protein. As with any protein, some of the spike's conformational motions are expected to be biophysically relevant, but cannot be interpreted only by static models. Using experimental cryo-EM images, we present the energy landscape of the glycosylated spike protein, and identify the diversity of low-energy conformations in the vicinity of its open (so called 1RBD-up) state. The resulting atomic refinement reveal global and local molecular rearrangements that cannot be inferred from an average 1RBD-up cryo-EM model. Here we report varied degrees of “openness” in global conformations of the 1RBD-up state, not revealed in the single-model interpretations of the density maps, together with conformations that overlap with the reported models. We discover how the glycan shield contributes to the stability of these low-energy conformations. Five out of six binding sites we analyzed, including those for engaging ACE2, therapeutic mini-proteins, linoleic acid, two different kinds of antibodies, switch conformations between their known apo- and holo-conformations, even when the global spike conformation is 1RBD-up. This apo-to-holo switching is reminiscent of a conformational preequilibrium. We found only one binding site, namely that of AB-C135 remains in apo state within all the sampled free energy-minimizing models, suggesting an induced fit mechanism for the docking of this antibody to the spike. |
| first_indexed | 2024-04-13T04:43:47Z |
| format | Article |
| id | doaj.art-f282bd28f44747318e59a3ad51827f3f |
| institution | Directory Open Access Journal |
| issn | 2665-928X |
| language | English |
| last_indexed | 2024-04-13T04:43:47Z |
| publishDate | 2022-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Current Research in Structural Biology |
| spelling | doaj.art-f282bd28f44747318e59a3ad51827f3f2022-12-22T03:01:55ZengElsevierCurrent Research in Structural Biology2665-928X2022-01-0146877Energy landscape of the SARS-CoV-2 reveals extensive conformational heterogeneityGhoncheh Mashayekhi0John Vant1Abhigna Polavarapu2Abbas Ourmazd3Abhishek Singharoy4Department of Physics, University of Wisconsin Milwaukee, 3135 N. Maryland Ave, Milwaukee, WI, 53211, USASchool of Molecular Sciences, Center for Applied Structural Discovery, Arizona State University, Tempe, AZ, 85287, USABIOVIA, Dassault Systèmes, 5005 Wateridge Vista Dr San Diego, CA, USADepartment of Physics, University of Wisconsin Milwaukee, 3135 N. Maryland Ave, Milwaukee, WI, 53211, USA; Corresponding authors.School of Molecular Sciences, Center for Applied Structural Discovery, Arizona State University, Tempe, AZ, 85287, USA; Corresponding authors.Cryo-electron microscopy (cryo-EM) has produced a number of structural models of the SARS-CoV-2 spike, already prompting biomedical outcomes. However, these reported models and their associated electrostatic potential maps represent an unknown admixture of conformations stemming from the underlying energy landscape of the spike protein. As with any protein, some of the spike's conformational motions are expected to be biophysically relevant, but cannot be interpreted only by static models. Using experimental cryo-EM images, we present the energy landscape of the glycosylated spike protein, and identify the diversity of low-energy conformations in the vicinity of its open (so called 1RBD-up) state. The resulting atomic refinement reveal global and local molecular rearrangements that cannot be inferred from an average 1RBD-up cryo-EM model. Here we report varied degrees of “openness” in global conformations of the 1RBD-up state, not revealed in the single-model interpretations of the density maps, together with conformations that overlap with the reported models. We discover how the glycan shield contributes to the stability of these low-energy conformations. Five out of six binding sites we analyzed, including those for engaging ACE2, therapeutic mini-proteins, linoleic acid, two different kinds of antibodies, switch conformations between their known apo- and holo-conformations, even when the global spike conformation is 1RBD-up. This apo-to-holo switching is reminiscent of a conformational preequilibrium. We found only one binding site, namely that of AB-C135 remains in apo state within all the sampled free energy-minimizing models, suggesting an induced fit mechanism for the docking of this antibody to the spike.http://www.sciencedirect.com/science/article/pii/S2665928X22000034Cryo-EMMolecular dynamicsFree energy landscapeManifold machine learningSpike protein |
| spellingShingle | Ghoncheh Mashayekhi John Vant Abhigna Polavarapu Abbas Ourmazd Abhishek Singharoy Energy landscape of the SARS-CoV-2 reveals extensive conformational heterogeneity Current Research in Structural Biology Cryo-EM Molecular dynamics Free energy landscape Manifold machine learning Spike protein |
| title | Energy landscape of the SARS-CoV-2 reveals extensive conformational heterogeneity |
| title_full | Energy landscape of the SARS-CoV-2 reveals extensive conformational heterogeneity |
| title_fullStr | Energy landscape of the SARS-CoV-2 reveals extensive conformational heterogeneity |
| title_full_unstemmed | Energy landscape of the SARS-CoV-2 reveals extensive conformational heterogeneity |
| title_short | Energy landscape of the SARS-CoV-2 reveals extensive conformational heterogeneity |
| title_sort | energy landscape of the sars cov 2 reveals extensive conformational heterogeneity |
| topic | Cryo-EM Molecular dynamics Free energy landscape Manifold machine learning Spike protein |
| url | http://www.sciencedirect.com/science/article/pii/S2665928X22000034 |
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