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I am reading the article How the coronavirus infects cells — and why Delta is so dangerous. It describes the fusion process of the virus into the host cell as follows right above an animation demonstrating the process.

First, TMPRSS2 cuts a site on the spike’s S2 subunit8. That cut exposes a run of hydrophobic amino acids that rapidly buries itself in the closest membrane — that of the host cell. Next, the extended spike folds back onto itself, like a zipper, forcing the viral and cell membranes to fuse.

Is the hydrophobic property of the hydrophobic amino acid crucial for the burying into the closest membrane and folding back onto itself? What is the physics of this mechanism?

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    $\begingroup$ The way you pose your question is problematic. First you appear to be asking two questions, one of which you demand to be answered with “detailed physics”. If that is so you would seem to be posting on the wrong site, although another interpretation is that you require an explanation of the “hydrophobic effect” — chemical thermodynamics of proteins, covered in the introductory chapters of biochemistry texts such as Berg or Lehninger. If this is the case (and the obviousness of the answer — yes the hydrophobic nature is crucial — suggests so), your question comes under the category “homework”. $\endgroup$
    – David
    Aug 5, 2021 at 20:50
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    $\begingroup$ Your second question, which, if valid for this site, needs to be posed separately. Again, it is not sure whether you are familiar with proteolytic enzymes in general (use of the word "cut" suggests perhaps not) and the frequent activation of proteins by hydrolysis of peptide bonds. Even if you are, the phenomenon is widespread in RNA viruses because of their tendency to synthesize polyproteins (for reasons discussed elsewhere on this site). There are numerous articles on the effect of proteolysis on Covid spike protein, suggesting you are not searching in an appropriate manner. Why not? $\endgroup$
    – David
    Aug 5, 2021 at 20:57
  • $\begingroup$ As you hace accepted an answer that only addresses one of the questions, and as the second should have been posted as a separate question I have edited your question and removed it. I have also cut unnecessary material about homework questions etc. as this has been addressed and is not part of the question. $\endgroup$
    – David
    Aug 13, 2021 at 17:17
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    $\begingroup$ Hey, @David--while I appreciate the edit to remove the close vote discussion from the question, I disagree with removing the part about the cleavage initiating the process. The answer does address this (see paragraph beginning: "The cleavage of spike is crucial..."). While the asker did write separate sentences ending in question marks, they both describe the same process, as fusion does not happen without cleavage. The original way the asker formatted the question (without the ordered list) makes the most sense to me. $\endgroup$
    – Luigi
    Aug 19, 2021 at 13:33
  • $\begingroup$ Happy to discuss this further in chat if you disagree! Just ping me and I can jump in. Will not edit in case you want to chat. $\endgroup$
    – Luigi
    Aug 19, 2021 at 13:33

1 Answer 1

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Interesting question! Yes, the hydrophobic amino acids are very important; they facilitate interaction with the hydrophobic (inner) portion of the lipid bilayer. A useful review focusing on the bilayer side that I'll reference throughout this answer is here: Mechanics of membrane fusion, doi: 10.1038/nsmb.1455.

(a) shows a model of two lipid bilayers fusing (minus protein contributions). Essentially, the spike makes this process thermodynamically favorable.

hemifusion of lipid bilayers

The hydrophobic residues are key because they are what enables the other end of the spike protein to interact with and deform the cell membrane. Here's a model of protein-mediated fusion from that same review (they emphasize that the deformation is key):

protein-mediated deformation

The cleavage of spike is crucial to initiate this process because the hydrophobic residues are not accessible/cannot interact with the cell membrane unless the spike has been cleaved. This works to the advantage of the virus, since if the spike is close enough to be cleaved by TMPRSS2, it's close enough to stab the membrane of the correct cell. A virus with hydrophobic residues that are always ready-to-go, in comparison, would likely fuse with a lot of random/off-target membranes of cells or vesicles that would not be permissive to viral replication.

Mechanisms of membrane fusion disparate players and common principles is a review paper.

A detailed discussion of the physics of this process is beyond the scope of this site, but here are some potential starting points (disclaimer: I am not a physicist):

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  • $\begingroup$ +1 and accepted. This is exactly the kind of answer I am looking for! Much appreciated! $\endgroup$
    – Hans
    Aug 7, 2021 at 2:59
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    $\begingroup$ I added one more physics reference that is more recent. Hope you do not mind. $\endgroup$
    – Hans
    Aug 12, 2021 at 16:09
  • $\begingroup$ Thanks, not at all! $\endgroup$
    – Luigi
    Aug 12, 2021 at 16:24
  • $\begingroup$ (+1) But to avoid confusion: if we consider the lipid membrane a bilayer, the interaction is with the hydrophobic portion of the outer layer of the bilayer? (And this is due to the 'oil in water' (or hydrophobic) effect) $\endgroup$
    – user338907
    Aug 12, 2021 at 18:37
  • $\begingroup$ Release of S1 trimer should be what allows conformational changes of S2 whose transition to lower energy state curves the membranes (assuming the fusion peptide anchored into the host membrane). pnas.org/content/114/42/11157 ncbi.nlm.nih.gov/pmc/articles/PMC7112261 There is more than one spike trimer involved, curving the membranes at different points together induces a hole and fusion of the two membranes. But it is very difficult to be sure because CryoEM doesn't fit well with membrane stuffs and conformational transitions. @Hans $\endgroup$
    – reuns
    Aug 12, 2021 at 23:30

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