Benjamin Brooks2
Member
27 messages
joined Jun 2020
Regarding these mutations
Researching that spike protein shows two different conformations.
Conformations are just different shapes a molecule takes when parts of it rotate around a single bond.
First, there's the closed conformation, where the virus struggles to fuse with a cell because conditions aren't ideal.
It has a low affinity for binding to the ACE2 receptor since there's less contact surface between the RBD and ACE2.
Once it hits the intercellular space in the human body, the spike is hit by
the cellular endoprotease furin, which shifts it into an open conformation. In this state, there's a high affinity for ACE2 due to the increased contact surface. Once it switches to open, the spike can't go back to being closed.
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Only a few months after the first SARS-CoV-2 cases popped up in Wuhan in December 2019, new strains started appearing. Within a short window, numerous mutations were spotted globally; by June 1, 2020, about 35,000 strains
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The D614G mutation
It's thought that replacing aspartate with glycine at position 614 speeds up how the S spike glycoprotein binds to the ACE2 receptor, making it easier to enter the cell.
In the study "The Effect of The D614G substitution on The structure of The spike glycoprotein of SARS-CoV-2", researchers found that 87% of the mutated spikes were in the open conformation, sometimes with one or two RBDs pushed out. By comparison, only 17% of the wild-type spikes were in the open conformation, while the rest stayed closed.
When the spike is stuck in the closed conformation, the RBD is physically blocked from interacting with the ACE2 receptor.
The G614 type mostly exists in a shape ready to bind to the receptor, so it doesn't even need furin to act on it—something the wild type needs to trigger the switch to the open conformation. Basically, the mutation removes a step in the entry mechanism, which significantly makes infecting cells easier.
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Proteins aren't static; they go through various conformational
changes that either stabilize or destabilize interactions at the amino acid level. These include non-covalent interactions, like the hydrophobic effect, which stabilize different conformations, and covalent ones that can stabilize or destabilize the structure.
D614
It was noted that aspartate (D) on monomer chain A (green) sits close enough (6.46 Å) to lysine (K) at position 854 B on monomer chain B (orange). This allows the negatively charged carboxyl group to create an attractive ionic interaction with the positively charged, protonated amino group of the lysine in the wild-type virus's closed conformation. To move to the open conformation, chains A and B have to pull apart so the RBD of chain B
can be pushed outward. That requires breaking several attractive interactions between the chains. Comparing the two, you have to overcome that attraction between the aspartate and lysine, requiring energy to push them far enough apart—specifically 8.25 Å—so the ionic bridge breaks.
Because of this interaction, the glycoprotein favors the closed conformation, staying in that shape about 83% of the time.
G614
With the mutation, the negatively charged aspartate is swapped for a neutral glycine. Since glycine is a tiny amino acid with no side chain, it can't maintain that interaction with the negatively charged lysine 854 B in the closed conformation.
It looks like glycine and lysine stay about the same distance apart—roughly 8.40 Å—whether they're in a closed or open conformation.
The idea is that the mutation kills off any stabilizing effect at position 614. Since there's less energy needed to flip into that open state under the right conditions, you barely
even need an enzyme to get it done. That’s why this mutated strain dominates at 87%, because it's much better at breaking into cells.
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The reason this mutant is more infectious? It's got more conformational freedom because that ionic pull between aspartate and lysine is gone—replaced by glycine.
😁
