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

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" />.

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default [[#Molecular Dynamics Simulation of Membrane Fusion]]

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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.

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>.

===Membrane Fusion Schematic===

[[Image:Fusion-schematic-hamilton-2012-mod1.png|700px]]

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<font color="gray">Lipid Bilayers</font>.

<font color="green">Receptor (ACE2 for SARS-CoV-2)</font>.

===Molecular Dynamics Simulation of Membrane Fusion===

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[[Image:Pabis-MDS-Fig1AD-Labeled.jpg|700px]]

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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.

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[[Image:Cai-zhang-fig-5a.png|350px]]

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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.

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==Preventing Fusion with Drugs==

SARS-CoV-2 spike protein has two interior cavities: (i) <scene name='85/857791/6zgi_translucent_backbone/2'>Show spike protein structure</scene> ([[6zgi]]) and then (ii)

<jmol>

'''[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]]

===Pre-Fusion Spike Protein===

==See Also==

*[[SARS-CoV-2 spike protein priming by furin]] - the step prior to membrane fusion.

*[[SARS-CoV-2 protein S]]

*[[Spike protein]]

*[[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]]

==Methods==

The pre-fusion structure [[6xr8]] was [[morph|morphed]] to the post-fusion structure [[6xra]] by linear interpolation, requesting 14 intermediate frames (16 total), using the [[Morphs#Linear_Morph_Server|server provided by Karsten Theis]] after another method<ref>Proteopedia's PyMOL morph server was used in both RigiMOL and linear modes, all atoms or only alpha carbon atoms. Rendering these as backbones or traces by Jmol gave broken lines. The reason for backbone breaking was not investigated further.</ref> gave unsatisfactory results. To avoid artifactual movement in the morph, prior to morphing, two changes were required in 6xra: (i) the names of chains B and C needed to be swapped (done with SwissPDBViewer), and (ii) the structure needed to be rotated +120° around the Z axis (Jmol "rotateselected" command). The morph was an 11 MB file, which took 25 sec to load into JSmol. Each script took a minimum of 8 sec to complete. To reduce both the bulk of this file and the processing times for JSmol, the alpha carbons were extracted (along with the MODEL and ENDMDL records) by deleting all other lines in the PDB file<ref name="cao">Selecting *.ca in the [[Jmol/Application|Jmol Java application]] and saving a PDB file produced a PDB file with numerous errors. The desired result was obtained with this command in macOS Terminal: <tt>sed -e /REMARK/d -e /HETATM/d -e /^ATOM\ \ [\ 0-9][0-9][0-9][0-9][0-9]\ \ [CONS][\ B-Z].*$/d <original.pdb >product.pdb</tt>.</ref>. The resulting 16 model morph PDB file is [[Image:Morf-6xr8-6xra-theis-cao.pdb]].

== References and Notes ==

<references/>