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SARS-CoV-2 spike protein fusion transformation: Difference between revisions

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SARS-CoV-2 spike protein undergoes a dramatic conformational rearrangement (<scene name='85/857791/Morf-6xr8-6xra-lin-theis-cao/5'>restore initial scene</scene>) that plays a central role in fusing the coronavirus membrane with the host cell membrane<ref name="cai-zhang">PMID: 32694201</ref>. Similar conformational transformations have been observed for the spike protein of SARS-CoV<ref name="fan">PMID: 32681106</ref> and mouse hepatitis virus<ref name="walls">PMID: 29073020</ref>, among others. These rearrangements also have much in common with the membrane fusion mechansism of influenza hemagglutinin<ref name="hamilton" /><ref name="pabis">PMID: 32188780</ref>. The molecular scenes in this article are based on the [[cryo-EM]] pre- and post-fusion structures of SARS-CoV-2 spike protein reported July, 2020, by Cai, Zhang and coworkers with the group of Bing Chen<ref name="cai-zhang" />.
SARS-CoV-2 spike protein undergoes a dramatic conformational rearrangement (<scene name='85/857791/Morf-6xr8-6xra-lin-theis-cao/5'>restore initial scene</scene>) that plays a central role in fusing the coronavirus membrane with the host cell membrane<ref name="cai-zhang">PMID: 32694201</ref>. Similar conformational transformations have been observed for the spike protein of SARS-CoV<ref name="fan">PMID: 32681106</ref> and mouse hepatitis virus<ref name="walls">PMID: 29073020</ref>, among others. These rearrangements also have much in common with the membrane fusion mechansism of influenza hemagglutinin<ref name="hamilton" /><ref name="pabis">PMID: 32188780</ref>. The molecular scenes in this article are based on the [[cryo-EM]] pre- and post-fusion structures of SARS-CoV-2 spike protein reported July, 2020, by Cai, Zhang and coworkers with the group of Bing Chen<ref name="cai-zhang" />.


{| width="650" class="wikitable"
{| width="550" class="wikitable"
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|colspan="3"|Click thumbnail images to jump to full sizes with explanations below:
|colspan="3"|Click thumbnail images to jump to full sizes with explanations below:
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<imagemap>
Image:Cai-zhang-fig-5a.png|150px
default [[#Spontaneous Fusion Transformation]]
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Image:Romeo-graphical-abstract-700px.jpg|150px
default [[#Preventing Fusion with Drugs]]
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| colspan="2" style="text-align:center;"|
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<imagemap>
Image:Pabis-MDS-Fig1AD-Labeled.jpg|250px
Image:Pabis-MDS-Fig1AD-Labeled.jpg|250px
default [[#Molecular Dynamics Simulation of Membrane Fusion]]
default [[#Molecular Dynamics Simulation of Membrane Fusion]]
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default [[#Spontaneous Fusion Transformation]]
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:(2) The virus membrane is attached near the <font color="red">'''red balls'''</font>. The <scene name='85/857791/Morf-6xr8-6xra-lin-theis-cao/7'>virus membrane appears to be pulled into close proximity to the host cell membrane</scene> (near the <font color="#0060ff">'''blue balls'''</font>), initiating membrane fusion. The virus membrane is brought closer than shown here: these models lack the stem. The <font color="red">'''red balls'''</font> would actually end up much closer to the <font color="#0060ff">'''blue balls'''</font> than these models show.
:(2) The virus membrane is attached near the <font color="red">'''red balls'''</font>. The <scene name='85/857791/Morf-6xr8-6xra-lin-theis-cao/7'>virus membrane appears to be pulled into close proximity to the host cell membrane</scene> (near the <font color="#0060ff">'''blue balls'''</font>), initiating membrane fusion. The virus membrane is brought closer than shown here: these models lack the stem. The <font color="red">'''red balls'''</font> would actually end up much closer to the <font color="#0060ff">'''blue balls'''</font> than these models show.


<center><i>Use the '''toggle animation''' button to restart animation as needed.<br>
<center><i>Use the '''toggle animation''' button above to restart animation as needed.<br>
Remember that a [[morph]] is intended to help you compare two structures. This morph does NOT portray a realistic transition pathway.</i></center>
Remember that a [[morph]] is intended to help you compare two structures. This morph does NOT portray a realistic transition pathway.</i></center>


:(3) The <scene name='85/857791/Morf-6xr8-6xra-lin-theis-cao/8'>middle portion of the spike protein remains relatively stable</scene>.
:(3) The <scene name='85/857791/Morf-6xr8-6xra-lin-theis-cao/8'>middle portion of the spike protein remains relatively stable</scene>.


An <jmol>
  <jmolLink>
    <script>load /images/0/09/Spike_SARS_CoV_2_storymorph.pdb; script /scripts/85/857791/Alternate_morph/1.spt;
            model 0; select protein and not (912,1162); backbone only; select all; backbone 0.8;
            select 912,1162; spacefill 4.0;
            anim on</script>
    <text>alternate pathway</text>
  </jmolLink>
</jmol> <ref>The [[Jmol/Storymorph|Storymorph Jmol scripts]] were used to create the interpolation shown in the morph. [https://proteopedia.org/wiki/index.php/Image:Spike_SARS_CoV_2_storymorph.pdb|Coordinates] available on Proteopedia</ref> between the two conformations shows how some secondary structure is retained while structural elements change orientation and position substantially. USe the button above to start and pause the morph.
<jmol>
  <jmolRadioGroup>
    <item>
      <script>model 0; select not (912, 1162); backbone only; backbone 0.8; model 1; anim on</script>
      <text>Lines</text>
      <checked>true</checked>
    </item>
    <item>
      <script>model 0; select not (912, 1162); spacefill only; spacefill 4.0; model 1; anim on</script>
      <text>Spheres</text>
      <checked>false</checked>
    </item>
  </jmolRadioGroup>
</jmol>
===Membrane Fusion Schematic===
===Membrane Fusion Schematic===


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[[Image:Fusion-schematic-hamilton-2012-mod1.png|700px]]
[[Image:Fusion-schematic-hamilton-2012-mod1.png|700px]]
</td></tr><tr><td><b>
</td></tr><tr><td><b>
Figure 1:
<font color="gray">Lipid Bilayers</font>.
<font color="gray">Lipid Bilayers</font>.
<font color="green">Receptor (ACE2 for SARS-CoV-2)</font>.
<font color="green">Receptor (ACE2 for SARS-CoV-2)</font>.
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===Molecular Dynamics Simulation of Membrane Fusion===
===Molecular Dynamics Simulation of Membrane Fusion===


Molecular dynamics simulations are consistent with this hypothesis. Below is shown a liposome containing influenza hemagglutinin fusing with a lipid bilayer in a molecular dynamics simulation<ref name="pabis" />.
[[Molecular dynamics simulations]] are consistent with this hypothesis. Below is shown a liposome containing influenza hemagglutinin fusing with a lipid bilayer in a molecular dynamics simulation<ref name="pabis" />.
<table style="border-collapse:collapse;border:1px solid black;width:700px;"><tr><td>
<table style="border-collapse:collapse;border:1px solid black;width:700px;"><tr><td>
[[Image:Pabis-MDS-Fig1AD-Labeled.jpg|700px]]
[[Image:Pabis-MDS-Fig1AD-Labeled.jpg|700px]]
</td></tr><tr><td>
</td></tr><tr><td>
Figure 2:
Results of a molecular dynamics simulation. Note the fusion peptides embedded in the lipid bilayer at left (green). Adapted from Fig. 1 by Pabis, Rawle and Kasson<ref name="pabis" />. Redistribution for non-commercial, educational purposes permitted under the [https://www.pnas.org/authors/fees-and-licenses PNAS License]. Appropriate use confirmed by Peter Kasson, August 8, 2020.
Results of a molecular dynamics simulation. Note the fusion peptides embedded in the lipid bilayer at left (green). Adapted from Fig. 1 by Pabis, Rawle and Kasson<ref name="pabis" />. Redistribution for non-commercial, educational purposes permitted under the [https://www.pnas.org/authors/fees-and-licenses PNAS License]. Appropriate use confirmed by Peter Kasson, August 8, 2020.
</td></tr></table>
</td></tr></table>
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[[Image:Cai-zhang-fig-5a.png|350px]]
[[Image:Cai-zhang-fig-5a.png|350px]]
</td></tr><tr><td>
</td></tr><tr><td>
Figure 3: Virion with mixture of pre- and post-fusion spike protein conformations, in the absence of ACE2.
Fig. 5A (cropped) from Cai, Zhang and coworkers<ref name="cai-zhang" /> reproduced in accord with the [https://creativecommons.org/licenses/by/4.0/ Creative Commons Attribution 4.0 International] license specified in ''Science''. Permission also given by Bing Chen, August 7, 2020.
Fig. 5A (cropped) from Cai, Zhang and coworkers<ref name="cai-zhang" /> reproduced in accord with the [https://creativecommons.org/licenses/by/4.0/ Creative Commons Attribution 4.0 International] license specified in ''Science''. Permission also given by Bing Chen, August 7, 2020.
</td></tr></table>
</td></tr></table>
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[[Image:Romeo-graphical-abstract-700px.jpg|350px]]
[[Image:Romeo-graphical-abstract-700px.jpg|350px]]
</td></tr><tr><td>
</td></tr><tr><td>
Graphical Abstract from Romeo, Iacovelli & Falconi<ref name="romeo" /> reproduced in accord with the COVID-19 pandemic license of Elsevier<ref name="elsevier">This quote is from the PubMedCentral version of the Romeo paper, after you click ''License Information'': Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.</ref>. Permission also given by Mattia Falconi, August 12, 2020.
Figure 4:
Graphical Abstract from Romeo, Iacovelli & Falconi<ref name="romeo" /> reproduced in accord with the COVID-19 pandemic license of Elsevier<ref name="elsevier">This quote is from the PubMedCentral version of the Romeo paper, after you click ''License Information'': "Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active."</ref>. Permission also given by Mattia Falconi, August 12, 2020.
</td></tr></table>
</td></tr></table>


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'''[http://proteopedia.org/wiki/images/6/67/Spike_protein_fusion_mainchain_morph_from_Proteopedia.Org.gif Download] (right click, save link as)''' 500 px wide main chain animation. This shows a smoothed main chain (backbone) trace. Please credit '''Proteopedia.Org''' in accord with our [[Proteopedia:Terms of Service|license]], and '''Cai, Zhang and coworkers<ref name="cai-zhang" />''' for their cryo-EM structures.<br>
'''[http://proteopedia.org/wiki/images/6/67/Spike_protein_fusion_mainchain_morph_from_Proteopedia.Org.gif Download] (right click, save link as)''' 500 px wide main chain animation. This shows a smoothed main chain (backbone) trace. Please credit '''Proteopedia.Org''' in accord with our [[Proteopedia:Terms of Service|license]], and '''Cai, Zhang and coworkers<ref name="cai-zhang" />''' for their cryo-EM structures.<br>
[[Image:Spike protein fusion mainchain morph from Proteopedia.Org.gif]]
[[Image:Spike protein fusion mainchain morph from Proteopedia.Org.gif]]
===Alternate Pathway for Transformation===
Given that a [[morph]] is intended to help you compare two structures and does not portray a realistic transition pathway, there are many pathways we can imagine. Below is another one that has structural elements swing away from the core structure in a hinge motion as they change conformation. Another choice in this morph is to have different timings for the distinct changes to be able to follow them one at a time.
In the morph at full resolution, you can see a large cavity disappearing, the beta sheets acquiring an additional strand from a different subunit (subunits shown in green, blue and red tints), and changes in the core helix bundle along with the formation of the coiled-coil protrusion made of three helices.
'''[https://proteopedia.org/wiki/images/e/ef/Spike_storymorph.gif Download] (right click, save link as)''' 720 px wide main chain animation. This shows a smoothed main chain (backbone) trace. Please credit '''Proteopedia.Org''' in accord with our [[Proteopedia:Terms of Service|license]], and '''Cai, Zhang and coworkers<ref name="cai-zhang" />''' for their cryo-EM structures.<br>
[[Image:Spike labeled small.gif]]
'''[https://proteopedia.org/wiki/images/3/34/Spike_labeled_spacefill.gif Download] (right click, save link as)''' 720 px wide main chain animation. This shows C-alpha atoms as large spheres. Please credit '''Proteopedia.Org''' in accord with our [[Proteopedia:Terms of Service|license]], and '''Cai, Zhang and coworkers<ref name="cai-zhang" />''' for their cryo-EM structures.<br>
[[Image:Spike labeled spacefill small.gif]]


===Pre-Fusion Spike Protein===
===Pre-Fusion Spike Protein===
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==See Also==
==See Also==
*[[SARS-CoV-2 spike protein priming by furin]] - the step prior to membrane fusion.
*[[SARS-CoV-2 spike protein priming by furin]] - the step prior to membrane fusion.
*[[SARS-CoV-2 spike protein mutations]] suspected to increase transmission rates.
*[[SARS-CoV-2 protein S]]
*[[SARS-CoV-2 protein S]]
*[[Spike protein]]
*[[Spike protein]]
*[[Coronavirus Disease 2019 (COVID-19)]]
*[[Coronavirus Disease 2019 (COVID-19)]]
*[[User:Andre Wu Le Chun/Sandbox 1|Prefusion 2019-nCoV spike glycoprotein with a single receptor-binding domain up]] about [[6vsb]]
*[[User:Andre Wu Le Chun/Sandbox 1|Prefusion 2019-nCoV spike glycoprotein with a single receptor-binding domain up]] about [[6vsb]]
*[[Jmol/Cavities pockets and tunnels]]
*[[Cavity programs]]


==Methods==
==Methods==
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[[6zgi]] was loaded into the [[Jmol/Application|Jmol Java application]] (~11-fold faster than [[JSmol]]), and rendered as translucent backbone, each chain a different pastel color. The command
[[6zgi]] was loaded into the [[Jmol/Application|Jmol Java application]] (~11-fold faster than [[JSmol]]), and rendered as translucent backbone, each chain a different pastel color. The command
:<tt>isosurface minset 100 interior cavity 3.0 10.0</tt>
:<tt>isosurface minset 100 interior cavity 3.0 10.0</tt>
was executed (~45 sec). The numeric parameters in that command were determined by trial and error (see [[Jmol/Cavities pockets and tunnels]]). The cavity surface data were saved as Jmol voxel data, and uploaded to Proteopedia as [[Image:6zgi-cavities.jvxl]]. The button above reads that file to quickly display the interior cavity surface data.
was executed (~45 sec). The numeric parameters in that command were determined by trial and error (see [[Jmol/Cavities pockets and tunnels]]). The cavity surface data were saved as Jmol voxel data, and uploaded to Proteopedia as [[Image:6zgi-cavities.jvxl]]. The button above reads that file, rather than re-calculating the cavities, in order to display the interior cavity surface data much more quickly. See also [[Jmol/Cavities pockets and tunnels]].


==Acknowledgement==
Eric Martz thanks Deborah Spitz for a critique that improved this article.




== References and Notes ==
== References and Notes ==
<references/>
<references/>

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

Eric Martz, Karsten Theis
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